Anilide compounds and drugs containing the same

ABSTRACT

The invention relates to a novel anilide compound and a pharmaceutical composition comprising the same. The invention relates to a compound represented by the following general formula:                    
     represents a divalent residue of benzene with a substituent(s), heterocycle-condensed benzene which may or may not have a substituent, pyridine which may or may not have a substituent, cyclohexane or naphthalene                    
     Ar represents an aryl group which may or may not have a substituent, 
     X represents —NH—, oxygen atom or sulfur atom; 
     Y represents —NR 4 —, oxygen atom, sulfur atom, sulfoxide or sulfone; 
     Z represents single bond or —NR 5 —; 
     R 4  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent; 
     R 5  represents hydrogen atom, a lower alkyl group, an aryl group or a silylated lower alkyl group which may or may not have a substituent; and 
     n represents an integer of 0 to 15. 
     The inventive compounds are useful in the form of pharmaceutical composition, specifically as acyl coenzyme A cholesterol acyltransferase (ACAT) inhibitor.

This application is a divisional of application(s) application No. U.S.Ser. No. 09/381,850, filed on Dec. 6, 1999, now U.S. Pat. No. 6,362,208,which is a 371 of PCT/JP98/01337 filed on Mar. 25, 1998.

TECHNICAL FIELD

The present invention relates to a novel anilide compound and apharmaceutical composition containing the same. More specifically, theinvention relates to a compound represented by the general formula I:

represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene

Ar represents an aryl group which may or may not have a substituent;

X represents —NH—, oxygen atom or sulfur atom;

Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide or sulfone;

Z represents single bond or —NR₅—;

R₄ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent;

R₅ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent; and

n represents an integer of 0 to 15;

a salt thereof or a solvated compound thereof and pharmaceuticalcompositions comprising these compounds.

BACKGROUND OF THE INVENTION

Following the transfer of the (Japanese) dietary life to European-stylediets comprising high calorie and high cholesterol due to theimprovement of the living standard and the increase of the ratio of agedpeople in the (Japanese) population, hyperlipidemia and arterioscleroticdiseases caused by hyperlipidemia have increased in number rapidly inrecent years. The increase of these diseases is now one of the socialproblems (in Japan). Conventional pharmaceutical treatment ofhyperlipidemia and arteriosclerosis has mainly targeted the reduction oflipid in blood as the etiology thereof. The treatment has never targetedarteriosclerotic lesions of themselves. Acyl coenzyme A cholesterolacyltransferase (ACAT) is the enzyme to catalyze the synthesis ofcholesterol ester from cholesterol to play a significant role in thecholesterol metabolism and absorption in gastrointestinal tract. It issuggested that the inhibition of ACAT esterifying free cholesterol inthe epidermal cell of small intestine works to inhibit cholesterolabsorption from intestinal lumen and that the inhibition of cholesterolester generation in liver owing to ACAT inhibition suppresses VLDLsecretion from liver into blood stream, with the resultant action todecrease blood cholesterol. It is considered that many of conventionalACAT inhibitors function as anti-lipidemia agents to exert the action ofdecreasing blood cholesterol by allowing the inhibitors to react withthe ACAT enzyme in small intestine and liver.

As ACAT inhibitors, for example, U.S. Pat. No. 4,716,175 describes 2,2dimethyl-N-(2,4,6-trimethoxyphenyl)dodecanamide; and EP 372, 445describesN′-(2,4-difluorophenyl)-N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptylurea in the specification. However, many of these conventional ACATinhibitors as anti-hyperlipidemia agents principally work to decreaseblood cholesterol and are administered at large doses to permitsufficient exertion of the action. Due to the emergence of side effectsincluding intestinal bleeding, intestinal disorders, diarrhea and liverdisorders at high frequencies at clinical test stages, accordingly, thedevelopment of these agents for clinical practice has been verydifficult.

Arteriosclerosis is a disease essentially involving unique features ofhypertrophy of inner vascular membrane and lipid accumulation. Recentresearch works indicate that suppression of macrophage foamingessentially functioning for the formation of arteriosclerotic lesionspossibly degenerates arteriosclerotic lesions. Macrophage-derived foamcell (storing cholesterol ester as lipid droplet inside the cell) isobserved in arteriosclerotic lesions. It is indicated that macrophagefoaming is deeply involved in the progress of the disease. Additionally,it is reported that ACAT activity is elevated in the wall of blood tubesin arteriosclerotic lesions, indicating that cholesterol ester isaccumulated in the wall of blood tubes (Gyres, P. J. et al., Exp. Mole.Pathol., 44, 329-339 (1986)).

Due to the inhibition of cholesterol esterification by ACAT inhibitors,free cholesterol is generated inside cells and is then eliminated withhigh-density lipoprotein (HDL) to be transferred to and metabolized inliver (reverse transfer by HDL). It is suggested that the accumulationof cholesterol in diseased sites is thereby suppressed. Consequently,direct anti-arteriosclerotic action is exerted. A report tells that ACATincludes two sub-types, namely an ACAT type present in small intestineand an ACAT type, present in vascular wall (Quinoonen, P. M. et al.,Biochem., 27, 7344-7350 (1988)). Conventional research works on ACATinhibitors have mostly been carried out by using the ACAT type presentin small intestine and liver (Tomoda, H. et al., J. Antibiotics 47,148-153 (1994)). Based on the assumption that a pharmaceutical agentselectively inhibiting the ACAT type which presents in vascular wall maywork as a therapeutic agent of arteriosclerosis with less side effects,the present inventors have synthetically produced such inhibitors andhave carried out examinations on them.

DISCLOSURE OF THE INVENTION

So as to attain the object, the inventors have made investigations.Consequently, the inventors have found that a compound represented bythe general formula I:

represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene

Ar represents an aryl group which may or may not have a substituent;

X represents —NH—, oxygen atom or sulfur atom;

Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide or sulfone;

Z represents single bond or —NR₅—;

R₄ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent;

R₅ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent; and

n represents an integer of 0 to 15;

a salt thereof or a solvated compound thereof exerts an excellent ACATinhibitory action. Thus, the invention has been achieved.

The inventors have found that the inventive compounds exert ACATinhibitory actions in an organ-specific manner and an action inhibitingthe transfer of intra-cellular cholesterol and that the inventivecompounds are particularly useful as anti-hyperlipidemia agents with anexcellent action to reduce cholesterol in blood and as a prophylacticand therapeutic agent of arteriosclerosis with an action to suppressmacrophage foaming.

Thus, the compound represented by the general formula I, a salt thereofor a solvated product thereof is provided in accordance with theinvention.

Additionally, the invention provides pharmaceutical compositionscomprising the compound represented by the general formula I, a saltthereof or a solvated product thereof, together with carrierspharmaceutically acceptable.

Still additionally, the invention provides the compounds shown as theabove formula I, salts thereof or solvated compounds thereof, and ACATinhibitors, agents inhibiting intra-cellular cholesterol transfer, bloodcholesterol-reducing agents, or macrophage foaming-suppressing agents.In other words, the invention provides therapeutic and prophylacticagents of diseases including hyperlipidemia, arteriosclerosis,arteriosclerosis of carotid and cerebral arteries, cerebrovasculardiseases, ischemic cardiac diseases, coronary arteriosclerosis,nephrosclerosis, arteriosclerotic nephrosclerosis, arteriocapillarysclerotic nephrosclerosis, malignant nephrosclerosis, ischemicintestinal diseases, acute mesenteric blood tube occlusion, chronicintestinal angina, ischemic colitis, aortic aneurysm and occlusivearteriosclerosis (ASO).

As compounds similar to the compound of the formula I,3-(benzothiazol-2-ylthio)-N-(phenyl)propanamide and3-(benzoxazol-2-ylthio)-N-(phenyl)propanamide are disclosed in J. Chem.Eng. Data, 27, 207 (1982) and Fungitsidy, Ed. Melnilov, N. N. Izd. FanUzb. SSR: Tashkent, USSR. 82-88 (1980), respectively. However, it hasabsolutely never been known that these compounds exert ACAT inhibitoryactions.

BEST MODE FOR CARRYING OUT THE INVENTION

Preferable examples of the compound represented by the general formula Iin accordance with the invention include a compound represented by thefollowing formula II, a salt thereof or a solvated product thereof, anda compound represented by the following formula III, a salt thereof or asolvated product thereof:

represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene

X represents —NH—, oxygen atom or sulfur atom;

Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide or sulfone;

Z represents single bond or —NR₅—,

R₁, R₂ and R₃ may be the same or different and represent hydrogen atom,a lower alkyl group, a lower alkoxyl group, halogen atom, hydroxylgroup, phosphate group, sulfonamide group, or amino group which may ormay not have a substituent; otherwise, any combination of two of R₁, R₂and R₃ represents an alkylene dioxy group;

R₄ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent;

R₅ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent; and

n represents an integer of 0 to 15;

wherein

X represents —NH—, oxygen atom or sulfur atom;

Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide or sulfone;

Z represents single bond or —NR₅—;

R₁, R₂ and R₃may be the same or different and represent hydrogen atom, alower alkyl group, a lower alkoxyl group, halogen atom, hydroxyl group,phosphate group, sulfonamide group, or amino group which may or may nothave a substituent; otherwise, any combination of two of R₁, R₂ and R₃represents alkylene dioxy group;

R₄ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent;

R₆, R₇ and R₈ may be the same or different and represent hydrogen atom,a lower alkyl group which may or may not have a substituent, a loweralkoxyl group which may or may not have a substituent, halogen atom,hydroxyl group, carboxyl group, an alkoxycarbonyl group which may or maynot have a substituent, an alkylcarbonyloxy group which may or may nothave a substituent, an alkylcarbonyl group which may or may not have asubstituent, carbamoyl group which may or may not have a substituent, ahydroxyalkyl group, phosphate group, cyano group, nitro group,sulfonamide group, amino group which may or may not have a substituent,an aminoalkyl group which may or may not have a substituent, or aheterocyclic residue; otherwise, any combination of two of R₆, R₇ and R₈represents an alkylene dioxy group, provided that R₆, R₇ and R₈ neversimultaneously represent hydrogen atom;

and

n represents an integer of 0 to 15. More preferable is a compoundrepresented by the following general formula IV, a salt thereof or asolvated product thereof:

X represents —NH—, oxygen atom or sulfur atom;

Y represents —NR₄—, oxygen atom, sulfur atom, sulfoxide or sulfone;

Z represents single bond or —NR₅—;

R₁, R₂ and R₃may be the same or different and represent hydrogen atom, alower alkyl group, a lower alkoxyl group, halogen atom, hydroxyl group,phosphate group, sulfonamide group, or amino group which may or may nothave a substituent; otherwise, any combination of two of R₁, R₂ and R₃represents an alkylene dioxy group;

R₄ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent;

R₅ represents hydrogen atom, a lower alkyl group, an aryl group or asilylated lower alkyl group which may or may not have a substituent;

R₉, R₁₀, R₉′, R₁₀′, R₉″, R₁₀″, R₉′″, and R₁₀′″ may be the same ordifferent and represent hydrogen atom, a lower alkyl group which may ormay not have a substituent, a lower alkoxyl group which may or may nothave a substituent, halogen atom, hydroxyl group, carboxyl group, analkoxycarbonyl group which may or may not have a substituent, analkylcarbonyloxy group which may or may not have a substituent, analkylcarbonyl group which may or may not have a substituent, carbamoylgroup which may or may not have a substituent, a hydroxyalkyl group,phosphate group, sulfonamide group, amino group which may or may nothave a substituent, an aminoalkyl group which may or may not have asubstituent, or a heterocyclic residue; otherwise, any combination oftwo thereof represents an alkylene dioxy group;

and

n represents an integer of 0 to 15.

Ar in the general formula I represents an aryl group which may or maynot have a substituent; a specifically preferable group is the followinggroup:

wherein R₁, R₂ and R₃ may be the same or different and representhydrogen atom, a lower alkyl group, a lower alkoxyl group, halogen atom,hydroxyl group, phosphate group, sulfonamide group, or amino group whichmay or may not have a substituent; otherwise, any combination of two ofR₁, R₂ and R₃ represents an alkylene dioxy group.

The following group in the general formula I

represents a divalent residue of benzene with a substituent(s),heterocycle-condensed benzene which may or may not have a substituent,pyridine which may or may not have a substituent, cyclohexane ornaphthalene, or

A divalent residue of benzene with a substituent preferably includes thegroup represented by the following formula:

wherein R₆, R₇, and R₈ may be the same or different and representhydrogen atom, a lower alkyl group which may or may not have asubstituent, a lower alkoxyl group which may or may not have asubstituent, halogen atom, hydroxyl group, carboxyl group, analkoxycarbonyl group which may or may not have a substituent, analkylcarbonyloxy group which may or may not have a substituent, analkylcarbonyl group which may or may not have a substituent, carbamoylgroup which may or may not have a substituent, a hydroxyalkyl group,phosphate group, cyano group, nitro group, sulfonamide group, aminogroup which may or may not have a substituent, an aminoalkyl group whichmay or may not have a substituent, or a heterocyclic residue; otherwise,any combination of two of R₆, R₇, and R₈ represents alkylene dioxygroup, provided that R₆, R₇, and R₈ never simultaneously representhydrogen atom.

A divalent residue of heterocycle-condensed benzene which may or may nothave a substituent preferably includes the group represented by thefollowing formula:

wherein R₆ and R₇ may be the same or different and represent thosedescribed above; the ring B represents a saturated or unsaturatedheterocyclic group with at least one oxygen atom, nitrogen atom orsulfur atom in a 5- to 7-membered ring condensed with benzene ring.

A divalent residue of pyridine preferably includes the group representedby the formula:

wherein R₉, R₁₀, R₉′, R₁₀′, R₉″, R₁₀″, R₉′″, and R₁₀′″ may be the sameor different and represent hydrogen atom, a lower alkyl group which mayor may not have a substituent, a lower alkoxyl group which may or maynot have a substituent, halogen atom, hydroxyl group, carboxyl group, analkoxycarbonyl group which may or may not have a substituent, analkylcarbonyloxy group which may or may not have a substituent, analkylcarbonyl group which may or may not have a substituent, carbamoylgroup which may or may not have a substituent, a hydroxyalkyl group,phosphate group, sulfonamide group, amino group which may or may nothave a substituent, an aminoalkyl group which may or may not have asubstituent, or a heterocyclic residue; otherwise, any combination oftwo thereof represents an alkylene dioxy group.

The aryl group in R₄ and R₅ is preferably phenyl group, naphthyl groupand the like; and these aryl groups may or may not have the substituentsdescribed above.

The lower alkyl group represented by each symbol in the general formulaI preferably includes a linear or branched alkyl group with one to 15carbon atoms, preferably one to 10 carbon atoms and more preferably oneto 6 carbon atoms. For example, the lower alkyl group is preferablymethyl group, ethyl group, n-propyl group, iso-propyl group, n-butylgroup, iso-butyl group, tert-butyl group, n-pentyl group, n-hexyl groupor the like. As the lower alkoxyl group, preference is given to analkoxyl group comprising alkyl groups such as those described above. Thealkoxycarbonyl group preferably contains the alkoxyl groups describedabove. The alkylcarbonyloxy group preferably contains the lower alkylgroups described above. The alkylcarbonyl group preferably contains thelower alkyl groups described above.

Additionally, the lower alkyl groups, the lower alkoxyl groups, thealkoxycarbonyl groups, the alkylcarbonyloxy groups, the alkylcarbonylgroups or the carbamoyl groups may or may not have substituents. Thesesubstituents may work as alternative substituents for each other; forexample, alkoxy lower alkyl group, alkoxyalkoxyl group, loweralkoxyalkoxycarbonyl groups, alkoxycarbonyl-substituted alkyl group,alkoxycarbonyl-substituted alkoxyl group, alkoxycarbonyl-substitutedalkoxycarbonyl group may be possible.

Still additionally, other substituents include for example halogen atomssuch as chlorine atom and fluorine atom, hydroxyl group, silyl groupssuch as trimethylsilyl group, dimethyl t-butylsilyl group, anddimethylphenylsilyl group, saturated or unsaturated heterocyclicresidues containing one or two or more oxygen atoms, nitrogen atoms orsulfur atoms in the ring thereof, such as oxethanyl group,tetrahydrofuryl group and pyrrolidinyl group. The alkylene dioxy grouppreferably contains a linear or branched alkylene group with one to 6carbon atoms.

The halogen atom is preferably fluorine atom, chlorine atom, bromineatom or iodine atom or the like. The amino group may or may not besubstituted with one or two substituents. The substituents for the aminogroup preferably include lower alkyl groups such as those describedabove, aryl groups such as phenyl group and naphthyl group, and aralkylgroups such as benzyl group and phenethyl group; and the aromatic ringsthereof may or may not be substituted with lower alkyl groups and loweralkoxyl groups such as those described above, additionally. Furthermore,two of the substituents for the amino group together may form a 5- to7-membered ring which may or may not contain oxygen, sulfur or nitrogen.The heterocyclic residues are preferably of a monocycle, a polycycle ora condensed ring comprising a 5- to 7-membered ring, saturated orunsaturated, containing one or two hetero-atoms, preferably one to fourhetero-atoms such as oxygen atom, nitrogen atom or sulfur atom; andthese heterocyclic residues may or may not be substituted with the loweralkyl groups, the lower alkoxyl groups, the alkylene dioxy groups,halogen atom, the amino group, and substituted amino groups. Theheterocyclic residues include for example tetrazolyl group, 2-, 4- or5-imidazolyl group, 3- or 4-pyrazolyl group, 2-, 4- or 5-oxazolyl group,2-, 4- or 5-thiazolyl group, oxazolin-2-, 4- or 5-yl group,[1,3]-dioxylan-2- or 4-yl group, and these heterocyclic residuessubstituted with lower alkyl groups such as methyl group and ethylgroup.

The acid addition salt of the compound I in accordance with theinvention includes for example salts thereof with inorganic acids, suchas hydrochloride salt, sulfate salt, nitrate salt, and phosphate salt,and salts thereof with organic acids, such as methanesulfonate salt,maleate salt, fumarate salt and citrate salt.

Additionally, the solvated product thereof is prepared by addingsolvents used for the production and purification thereof, for examplewater and alcohol, to the compound I, with no specific limitation, aslong as the solvated product never disadvantageously affects the ACATinhibitory action. The solvated product is preferably a hydrated productthereof.

The invention relates to the compound represented by the generalformulae I, II, III or IV, a salt thereof or a solvated product thereof,and a pharmaceutical composition comprising the same and apharmaceutically acceptable carrier. More specifically, the inventionrelates to a pharmaceutical composition as ACAT inhibitor,intra-cellular cholesterol transfer inhibitory agent, bloodcholesterol-reducing agent, or macrophage foaming-suppressing agent.Still furthermore, the invention relates to a pharmaceutical compositionas a prophylactic and therapeutic agent of hyperlipidemia,arteriosclerosis, cerebrovascular diseases, ischemic cardiac disorders,ischemic colon disorders or aortic aneurysm.

Still additionally, the invention relates to a method fortherapeutically treating diseases due to ACAT, intra-cellularcholesterol transfer, blood cholesterol or macrophage foaming and amethod for therapeutically treating hyperlipidemia, arteriosclerosis,cerebrovascular diseases, ischemic cardiac disorders, ischemic colondisorders or aortic aneurysm, comprising administering a therapeuticallyeffective dose of the compound represented by the general formula I, II,III or IV, a salt thereof or a solvated product thereof.

Still more additionally, the invention relates to the use of thecompound represented by the general formula I, II, III or IV, a saltthereof or a solvated compound thereof for producing an ACAT inhibitor,an agent inhibiting intra-cellular cholesterol transfer, an agentreducing blood cholesterol, or an agent suppressing macrophage foamingand the use thereof for therapeutically treating hyperlipidemia,arteriosclerosis, cerebrovascular diseases, ischemic cardiac disorders,ischemic colon disorders or aortic aneurysm.

The compound I can be produced by a variety of known methods, with nospecific limitation. The compound I can be produced for example by thefollowing steps.

1. Process of Producing Compound with Z Representing Single Bond

(1) Following the reaction scheme described hereinbelow, reaction ofcarboxylic acid represented by the general formula V or a reactivederivative thereof, for example acid halide, with amine represented bythe general formula VI generates an amide derivative represented by thegeneral formula VII. Reaction of the resulting compound represented bythe general formula VII with a compound represented by the generalformula VIII can generate the objective compound I′ with Z representingsingle bond:

wherein R₁₁ represents an elimination group; and R₁₂ represents aresidue of a reactive derivative of hydroxyl group or carboxyl group.

A general method for peptide synthesis is applicable to the reaction ofthe compound V with the compound VI. R₁₁ in the general formula V ispreferably halogen atom such as chlorine atom and bromine atom; and theresidue of a reactive derivative as represented by R₁₂ is preferably anacid anhydride residue of mesyl acid, tosyl acid, acetic acid andpivalic acid. For example, the two compounds react together in thepresence of a condensing agent in a solvent whereby the objectivecompound can be recovered. As the condensing agent, use may be made offor example 1-(3′-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) and1,3-dicyclohexylcarbodiimide (DCC), singly or in combination with1-hydroxybenzotriazole (HOBt) and N-hydroxysuccinimide (HOSU). As thesolvent, use can be made of for example dimethylformamide, methylenechloride, chloroform, tetrahydrofuran and toluene, singly or incombination thereof, with no specific limitation.

The reaction varies, depending on the raw materials to be used; thereaction proceeds generally at 0 to 100° C., preferably around ambienttemperature, for one to 30 hours, preferably 10 to 20 hours. When ahighly reactive carboxylic halogenide is used as the compound V, thecompound V is allowed to react with the compound VI in the presence ofbases, for example triethylamine, 4-dimethylaminopyridine orN-methylmorpholine by general methods.

The starting compounds V and VI are known compounds; the compound V canbe produced by a method comprising oxidizing haloalkyl alcohol withJones reagents and the like, while the compound VI can be produced by amethod comprising subjecting a nitrobenzene derivative to a reductivereaction including contact reduction to prepare a corresponding anilinederivative.

The reaction of the compound VII thus recovered by the aforementionedmethods with the compound VIII can be progressed in the presence orabsence of bases in a solvent. As the solvent, use may be made of thosedescribed above, including bases for example inorganic bases includingalkali metal hydroxides such as sodium hydroxide and potassiumhydroxide, alkali metal carbonates such as sodium carbonate andpotassium carbonate, and alkali metal hydrogen carbonates such as sodiumhydrogen carbonate and potassium hydrogen carbonate; and organic basessuch as pyridine, triethylamine, N,N-diisopropylethylamine,N-methylmorpholine, and N,N-dimethylaniline.

(2) Following the reaction represented by the following scheme, thecompound represented by the general formula VIII is allowed to reactwith free carboxylic acid or an inactive carboxylic acid form as thecompound represented by the general formula V, to recover a carboxylatederivative represented by the general formula IX. The resulting compoundrepresented by the general formula IX or a reactive derivative thereof,for example an acid halide, is allowed to react with an anilinederivative represented by the general formula VI, to generate theobjective compound I′ with Z representing single bond:

wherein R₁₁ represents an elimination group and R₁₂ represents a residueof a reactive derivative of hydroxyl group or carboxyl group.

The reaction of the compound VIII with the compound V can be facilitatedby the second step described above in (1).

The reaction is progressed by using potassium hydroxide as the base andethanol as the solvent, preferably. The reaction of the compound VI withthe compound III can be facilitated by the first step described above in(1). If necessary, R₁₂ in the compound IX can be modified as a reactivederivative residue, prior to the reaction.

2. Process of Producing Compound I″ with Z Representing —NH—.

The compound represented by the general formula I wherein Z represents—NH— can be produced by a variety of methods. The compound can beproduced by the method represented by the following reaction scheme.

By allowing an isocyanate derivative represented by the general formulaX to react with an aniline derivative represented by the general formulaVI, a urea derivative represented by the general formula XI can berecovered.

By allowing the compound VIII to react with the resulting ureaderivative, the objective compound I″ with Z representing —NH— can berecovered.

As regards the reaction of the compound X with the compound VI at thefirst step, reaction of one to 2 equivalents of the compound VI with oneequivalent of the compound X in a solvent can yield the compound XI. Asthe solvent, preferably, use is made of for example methylene chloride,chloroform, ether, tetrahydrofuran, toluene, xylene, anddimethylformamide, with no specific limitation. The reaction progressesat 0° C. to the boiling point of the solvent used, over one to 24 hours.

The isocyanate derivative represented by the general formula X is aknown compound and can be produced, for example by a method comprisingallowing the carboxylic acid as the compound X to react withdiphenylphosphoryl azide in the presence of a base (the method byShioiri et al.) and a method en route of acid azide prepared by allowingan acid halide as the compound V to react with sodium azide.

The reaction of the compound XI with the compound VIII can befacilitated according to the second step of the reaction 1.1.

The intermediates and objective compounds as recovered in the individualreactions can be isolated and purified by purification methods routinelyused in synthetic organic chemistry, for example filtration, extraction,rinsing, drying, concentration, recrystallization, and variouschromatographic means. Furthermore, the intermediates can be subjected,with no purification, to next reaction.

The resulting compound I can be modified as an acid addition salt in aconventional manner.

Alternatively, solvated products thereof with solvents such as reactionsolvent and recrystallization solvent, specifically hydrated productthereof, may also be recovered.

Specific examples of the compounds recovered by the production methodsare shown in Tables 1, 2, 3, 4, 5, 6, 7 and 8.

TABLE 1 (I)

Example No.

X Y Z n Ar 1

O S * 5 2,6-diisopropylphenyl 2

O S * 5 2,6-diisopropylphenyl 3

O S * 5 2,6-diisopropylphenyl 4

O S * 5 2,6-diisopropylphenyl 5

NH S * 5 2,6-diisopropylphenyl 6

NH S * 5 2,6-diisopropylphenyl 7

O S * 8 2,6-diisopropylphenyl 8

O S * 8 2,6-diisopropylphenyl 9

O S * 8 2,6-diisopropylphenyl 10 

O S * 8 2,6-diisopropylphenyl 11 

O S * 5 2,6-diisopropylphenyl 12 

O S * 5 2,6-diisopropylphenyl *: Single Bond

TABLE 2 Example No.

X Y Z n Ar 13

O S * 5 2,6-diisopropylphenyl 14

O S * 5 2,6-diisopropylphenyl 15

O NR* * 5 2,6-diisopropylphenyl 16

O NMe * 5 2,6-diisopropylphenyl 17

O NH * 5 2,6-diisopropylphenyl 18

O NH * 5 2,6-diisopropylphenyl 19

O NH * 5 2,6-diisopropylphenyl 20

O NH * 5 2,6-diisopropylphenyl 21

S S * 5 2,6-diisopropylphenyl 22

O S * 5 2,6-diisopropylphenyl 23

O S * 5 2,6-diisopropylphenyl 24

O S * 5 2,6-diisopropylphenyl 25

O S * 5 2,6-diisopropylphenyl *: Single Bond R*:dimethylphenylsilylmethyl

TABLE 3 Example No.

X Y Z n Ar 26

O S * 5 2,6-diisopropylphenyl 27

O S * 5 2,6-diisopropylphenyl 28

O S * 5 2,6-diisopropylphenyl 29

O S * 5 2,6-diisopropylphenyl 30

O S * 5 2,6-diisopropylphenyl 31

O S * 8 2,6-diisopropylphenyl 32

O S * 5 2,6-diisopropylphenyl 33

O S * 8 2,6-diisopropylphenyl 34

O S * 5 2,6-diisopropylphenyl 34

O S * 5 2,6-diisopropylphenyl 36

O S * 5 2,6-diisopropylphenyl 37

O S * 5 2,6-diisopropylphenyl 38

O S * 5 2,6-diisopropylphenyl 39

O S * 5 2,6-diisopropylphenyl *: Single Bond

TABLE 4 Example No.

X Y Z n Ar 40

O S * 5 2,6-diisopropylphenyl 41

O S * 5 2,6-diisopropylphenyl 42

O S * 5 2,6-diisopropylphenyl 43

O S * 5 2,6-diisopropylphenyl 44

O S * 5 2,6-diisopropylphenyl 45

O S * 5 2,6-diisopropylphenyl 46

O S * 5 2,6-diisopropylphenyl 47

O S * 5 2,6-diisopropylphenyl 48

O S * 5 2,6-diisopropylphenyl 49

O S * 5 2,6-diisopropylphenyl 50

O S * 5 2,6-diisopropylphenyl 51

O S * 5 2,6-diisopropylphenyl *: Single Bond

TABLE 5 Example No.

X Y Z n Ar 52

O S * 5 2,6-diisopropylphenyl 53

S S * 1 2,6-diisopropylphenyl 54

O S * 8 2,6-diisopropylphenyl 55

O S —NH— 7 2,6-diisopropylphenyl 56

O SO —NH— 7 2,6-diisopropylphenyl 57

O S —NH— 7 2,6-diisopropylphenyl 58

O SO₂ * 5 2,6-diisopropylphenyl 59

O S * 5 2,6-diisopropylphenyl 60

O S * 5 2,6-diisopropylphenyl 61

O S * 5 2,4,6-trifluorophenyl 62

O S * 5 2,4,6-trimethoxy- phenyl *: Single Bond

TABLE 6 Example No.

X Y Z n Ar 63

NH S * 5 2,6-diisopropylphenyl 64

NH S * 5 2,6-diisopropylphenyl 65

S S * 5 2,6-diisopropylphenyl 66

O S * 5 2,6-diisopropylphenyl 67

O S * 5 2,6-diisopropylphenyl 68

NH S * 5 2,6-diisopropylphenyl 69

O S * 5 2,6-diisopropylphenyl 70

O S * 5 2,6-diisopropylphenyl 71

O S

6 2,6-diisopropylphenyl 72

O S

6 2,6-diisopropylphenyl 73

O S * 1 2,6-diisopropylphenyl 74

O S * 5 2,6-diisopropylphenyl 75

O S * 8 2,6-diisopropylphenyl *: Single Bond

TABLE 7 Example No.

X Y Z n Ar 76

O S * 5 2,6-diisopropylphenyl 77

O S * 5 2,6-diisopropylphenyl 78

O S * 5 2,6-diisopropylphenyl 79

O S * 5 2,6-diisopropylphenyl 80

O S * 5 2,6-diisopropylphenyl 81

O S * 5 2,6-diisopropylphenyl 82

O S * 5 2,6-diisopropylphenyl 83

O S * 5 2,6-diisopropylphenyl 84

O S * 5 2,6-diisopropylphenyl 85

O S * 5 2,6-diisopropylphenyl *: Single Bond

TABLE 8 Example No.

X Y Z n Ar 86

O S * 5 2,6-diisopropylphenyl 87

O S * 5 2,6-diisopropylphenyl 88

O S * 5 2,6-diisopropylphenyl 89

O S * 5 2,6-diisopropylphenyl 90

O S * 5 2,6-diisopropylphenyl 91

O S * 5 2,6-diisopropylphenyl 92

O S * 5 2,6-diisopropylphenyl *: Single Bond

The inventive compound represented by the general formula I has an ACATinhibitory action and/or an action inhibiting intra-cellular cholesteroltransfer and is therefore useful as a therapeutic agent ofhyperlipidemia or a therapeutic agent of arteriosclerosis in the fieldof clinical medicine. Particularly because the inventive compound exertsan action selectively inhibiting an ACAT type present in vascular wall,the inventive compound possibly exerts less side effects, compared withnon-selective ACAT inhibitors, which is preferable as an effectiveingredient of pharmaceutical agent.

The inventive pharmaceutical composition contains the compoundrepresented by the general formula I, an acid addition salt thereof or asolvated product thereof as the effective ingredient. Singly or incombination with other pharmaceutically acceptable carriers such asexcipients, binders and diluents, the effective ingredient can beprepared as dosage forms such as tablet, capsule, granule, powder,injection and suppository. These dosage forms can be produced accordingto known methods. For preparing an oral dosage form, the compoundrepresented by the general formula I is formulated with an appropriatecombination of excipients such as starch, mannitol and lactose, binderssuch as sodium carboxymethylcellulose and hydroxypropylcellulose,disintegrators such as crystal cellulose and carboxymethylcellulose,lubricants such as talc and magnesium stearate, and fluidity-enhancingagents such as light silicic anhydride.

The inventive pharmaceutical composition is administered orally orparenterally.

The dose of the inventive pharmaceutical composition varies, dependingon the body weight, age, sex and diseased conditions of a patient. Foran adult, generally, the compound represented by the general formula Iis preferably administered at 1 to 1000 mg, preferably 5 to 200 mg perday in one to three dividend doses.

The ACAT inhibitory action of the inventive compound represented by thegeneral formula I is tested in the following experimental examples.

Experimental Example 1 ACAT Inhibitory Action

In a conventional manner, microsome was prepared from the thoracic aortaof a rabbit fed with a 1% cholesterol diet for 8 weeks, which was thensuspended in 0.15 M phosphate buffer, pH 7.4, to prepare an enzymesolution. An enzyme solution was prepared from a rabbit small intestineon normal diet, which was defined as an enzyme solution derived fromsmall intestine.

The ACAT inhibitory activity was assayed by a modification of the methodby J. G. Hyder, J. Lipid Res., 24, 1127-1134 (1983). More specifically,2 μl of a test compound dissolved in dimethyl sulfoxide (DMSO) was addedto 88 μl of 0.15 M phosphate buffer, pH 7.4 containing ¹⁴C-Oleoyl-CoA(40 μM, 60,000 dpm) and 2.4 mg/ml bovine serum albumin, for incubationat 37° C. for 5 minutes. 10 μl of an enzyme solution was added to theresulting solution for reaction at 37° C. for 5 days (smallintestine-derived enzyme solution was subjected to reaction for 3minutes). Subsequently, the reaction was terminated by adding 3 ml ofchloroform/methanol (2/1) and 0.5 ml of 0.04 N hydrochloric acid to thereaction solution, to extract lipid. The solvent layer was concentratedand dried, which was then dissolved in hexane and spotted on a TLC plate(manufactured by Merck, Co.). The plate was eluted withhexane:ether:acetic acid (75:25:1). The radioactivity of the resultingcholesterol ester fraction was assayed by BAS 2000 (manufactured by FujiPhoto Film, Co., Ltd.). Compared with the radioactivity of a controlprepared by single addition of DMSO, IC₅₀ was determined. The resultsare shown in Table 9.

TABLE 9 A B C D  1 0.025 0.14 5.6  6 0.60 1.0 1.7 27 0.042 0.32 7.6 280.029 0.12 4.1 29 0.042 0.054 1.3 34 0.070 0.21 3.0 38 0.25 0.17 0.7 460.032 0.33 10.3 50 0.036 0.077 2.1 Control 1 0.45 0.87 1.9 Control 20.047 0.13 2.8 Control 3 0.034 0.056 1.7 Control 4 0.026 0.037 1.4 A:Test Compounds(Compounds of Examples) B: IC₅₀ (μM) of vascularwall-derived enzyme C: IC₅₀ (μM) of small intestine-derived enzyme D:IC₅₀ (μM) (for small intestine-derived enzyme)/IC₅₀ (μM) (for vascularwall-derived enzyme)

Experimental Example 2 ACAT Inhibitory Action (Anti-foaming Action) inJ1744 Cells and HepG2 Cells

J774 cells or HepG2 cells were inoculated on a 24-well plate; J774 cellsand HepG2 cells were cultured in DMEM and MEM culture broths (each ofthe broths containing 10% calf fetus serum), respectively, in a 5% CO₂incubator at 37° C. for 24 hours. These culture broths were individuallyexchanged to 0.5 ml of DMEM and MEM containing 10 μg/ml 25-OHcholesterol and a test sample, for 18-hr culturing. After discarding theculture media, the resulting cultures were rinsed twice with PBS andextracted with 1.5 ml of hexane:isopropanol (3:2), for concentration anddrying. The extracts were dissolved in isopropanol containing 0.2 ml of10% Triton X-100, to assay total cholesterol (TC) and free cholesterol(FC) by using Cholesterol E Test WAKO (manufactured by Wako PureChemicals, Co.) and Free Cholesterol E Test Wako (manufactured by WakoPure Chemicals, Co.). After extraction, cellular residue was solubilizedin 0.25 ml of 2 N NaOH at 37° C. for 30 minutes, to assay protein by BCAProtein Assay Reagent (Pierce). Based on the difference between TC andFC, cholesterol ester was calculated per protein, to determine IC₅₀,compared with the calculated control IC₅₀ value. The results are shownin Table 10.

TABLE 10 A B C D  1 1.30 4.1 3.2  6 10.0 10.0 1.0 27 1.31 — — 28 0.470.42 0.9 29 0.26 1.9 7.3 34 0.60 8.15 13.5 38 1.83 — — 46 0.098 29.76303.4 50 0.82 0.72 0.9 75 0.012 0.089 7.4 88 1.64 10.0 6.1 Control 10.56 5.30 9.5 Control 2 0.58 1.1 1.9 Control 3 0.32 1.3 4.3 Control 40.12 0.75 6.3 A: Test Compounds(Compounds of Examples) B: IC₅₀ (μM) ofJ774-derived enzyme C: IC₅₀ (μM) of HepG2-derived enzyme D: IC₅₀(HepG2)/IC₅₀(J774)

The following compounds were tested as control compounds by the samemethod. The results are shown in Tables 7 and 8.

Control 1:

5-[2-(2-(4-fluorophenyl)ethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-yl]oxy-2,2-dimethyl-N-(2,6-diisopropylphenyl)pentanamide(WO92/09582)

Control 2:

(+)-(S)-2-[5-(3,5-dimethylpyrazol-1-yl)pentasulfinyl]-4,5-diphenylimidazole(EP, A, 523941)

Control 3:

N-(2,2,5,5-tetramethyl-1,3-dioxan-4-ylcarbonyl)-β-alanine2(S)-[N′-(2,2-dimethylpropyl)-N′-nonylureido]-1(S)-cyclohexyl ester (EP,A, 421441)

Control 4:

[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-N-heptyl-2-benzoxazolamine(WO93/23392)

EXAMPLES

The inventive compounds are specifically described below. The inventionis not limited to these specific examples.

Example 1

Production of6-(oxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

Potassium carbonate (64 mg, 0.47 mmol) and 18-crown-6 (11 mg, 0.04 mmol)were added to a solution of 2-mercaptooxazolo[4,5-b]pyridine (64 mg,0.42 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (150 mg, 0.42mmol) in DMF (3 ml), and the resulting mixture was stirred at 80° C. for4 hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedwith water and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (elution solvents:hexane:ethyl acetate=2:1); theresulting crystal was recrystallized from ethyl acetate-hexane, torecover the objective compound of 49 mg (at a yield of 27%) as acolorless needle-like crystal.

Melting Point: 94-95° C. IR (KBr) cm⁻¹: 3230, 2965, 1646, 1497, 1403.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.52-1.68 (2H, m),1.68-1.82 (2H, m), 1.82-1.97 (2H, m), 2.33-2.45 (2H, m), 3.11 (2H, sept,J=6.8 Hz), 3.43 (2H, t, J=7.0 Hz), 7.12 (1H, d, J=8.1 Hz), 7.12 (1H, d,J=6.6 Hz), 7.22 (1H, dd, J=8.1, 6.6 Hz), 7.31 (1H, dd, J=8.1, 4.8 Hz)7.98 (1H, dd, J=8.1, 1.5 Hz), 8.42 (1H, d, J=4.8 Hz), 8.72 (1H, br s).EIMS m/z (relative intensity): 425 (M⁺), 407 (100). Elementary Analysis:C₂₄H₃₁N₃O₂S Required: C, 67.73; H, 7.34; N, 9.87; S, 7.53. Found: C,67.68; H, 7.33; N, 9.86; S, 7.57.

Example 2 Production of6-(oxazolo[4,5-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 1 except for the use of2-mercaptooxazolo[4,5-c]pyridine instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 126-127° C. IR (KBr) cm⁻¹: 3239, 2963, 1645, 1494, 1460.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.9 Hz), 1.52-1.65 (2H, m),1.67-1.80 (2H, m), 1.83-1.96 (2H , m), 2.33-2.43 (2H, m), 3.11 (2H,sept, J=6.9 Hz), 3.42 (2H, t, J=7.1 Hz), 7.12 (1H, d, J=8.3 Hz), 7.12(1H, d, J=6.9 Hz), 7.22 (1H, dd, J=8.3, 6.9 Hz), 7.66 (1H, dd, J=5.5,1.0 Hz) 8.49 (1H, d, J=5.5 Hz), 8.72 (1H, br s), 8.89 (1H, s). EIMS m/z(relative intensity): 425 (M⁺,100). Elementary Analysis: C₂₄H₃₁N₃O₂SRequired: C, 67.73; H, 7.34; N, 9.87; S, 7.53. Found: C, 67.65; H, 7.40;N, 9.59; S, 7.44.

Example 3 Production of6-(oxazolo[5,4-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 1 except for the use of2-mercaptooxazolo[5,4-c]pyridine instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 164-165° C. IR (KBr) cm⁻¹: 3227, 2963, 1652, 1482, 1115.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.53-1.67 (2H, m),1.67-1.82 (2H, m), 1.84-1.96 (2H, m), 2.33-2.42 (2H, m), 3.11 (2H, sept,J=6.8 Hz), 3.44 (2H, t, J=7.2 Hz), 7.12 (1H, d, J=8.4 Hz), 7.12 (1H, d,J=6.7 Hz), 7.22 (1H, dd, J=8.4, 6.7 Hz), 7.63 (1H, dd, J=5.4, 1.0 Hz)8.49 (1H, d, J=5.4 Hz), 8.71 (1H, br s), 8.89 (1H, d, J=0.7 Hz). EIMSm/z (relative intensity): 425 (M⁺), 230 (100). Elementary Analysis:C₂₄H₃₁N₃O₂S Required: C, 67.73; H, 7.34; N, 9.87, S, 7.53. Found: C,67.84; H, 7.43; N, 9.74, S, 7.51.

Example 4 Production of6-(oxazolo[5,4-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 1 except for the use of2-mercaptooxazolo[5,4-b]pyridine instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 146-147° C. IR (KBr) cm⁻¹: 3252, 2967, 1648, 1492, 1207.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.53-1.67 (2H, m),1.67-1.81 (2H, m), 1.83-1.96 (2H, m), 2.43-2.55 (2H, m), 3.11 (2H, sept,J=6.8 Hz), 3.40 (2H, t, J=7.2 Hz), 7.12 (1H, d, J=8.6 Hz), 7.12 (1H, d,J=6.7 Hz), 7.22 (1H, dd, J=8.6, 6.7 Hz), 7.40 (1H, dd, J=7.8, 5.1 Hz)8.01 (1H, dd, J=7.8, 1.6 Hz), 8.22 (1H, dd, J=5.1, 1.6 Hz), 8.71 (1H, brs). EIMS m/z (relative intensity): 425 (M⁺), 176 (100). ElementaryAnalysis: C₂₄H₃₁N₃O₂S Required: C, 67.73; H, 7.34; N, 9.87; S, 7.53.Found: C, 67.84; H, 7.44; N, 9.63; S, 7.50.

Example 5 Production of6-(imidazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

Potassium carbonate (86 mg, 0.62 mmol) and 18-crown-6 (15 mg, 0.06 mmol)were added to a solution of 2-mercaptoimidazolo[4,5-b]pyridine (85 mg,0.56 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (200 mg, 0.56mmol) in DMF (4 ml), and the resulting mixture was stirred at 80° C. for4 hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedwith water and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (elution solvents:chloroform:methanol=100:1); theresulting crystal was recrystallized from chloroform-ethylacetate-hexane, to recover the objective compound of 73 mg (at a yieldof 31%) as a colorless needle-like crystal.

Melting Point: 227-229° C. IR (KBr) cm⁻¹: 3235, 2963, 1651, 1395, 1268.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.51-1.89 (6H, m), 2.38(2H, m), 3.11 (2H, sept, J=6.8 Hz), 3.36 (2H, t, J=7.1 Hz), 7.11 (1H,dd, J=8.3, 4.9 Hz), 7.11 (1H, d, J=8.3 Hz), 7.12 (1H, d, J=6.6 Hz), 7.22(1H, dd, J=8.3, 6.6 Hz), 7.77 (1H, d, J=8.3 Hz) 8.19 (1H, d, J=4.9 Hz),8.72 (1H, br s). EIMS m/z (relative intensity): 424 (M⁺), 165 (100).Elementary Analysis: C₂₄H₂N₄OS Required: C, 67.89; H, 7.60; N, 13.20; S,7.55. Found: C, 68.01; H, 7.62; N, 12.96; S, 7.41.

Example 6 Production of6-(imidazolo[4,5-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 5 except for the use of2-mercaptoimidazolo[4,5-c]pyridine instead of2-mercaptoimidazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 96-98° C. IR (KBr) cm⁻¹: 3231, 2962, 1649, 1463, 1278.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.51-1.89 (6H, m), 2.38(2H, m), 3.11 (2H, sept, J=6.8 Hz), 3.36 (2H, t, J=5.6 Hz), 7.12 (1H, d,J=8.3 Hz), 7.12 (1H, d, J=6.6 Hz), 7.22 (1H, dd, J=8.3, 6.6 Hz), 7.40(1H, dd, J=5.6, 1.0 Hz) 8.19 (1H, d , J=5.6 Hz), 8.70 (1H, d, J=1.0 Hz),8.71 (1H, br s). EIMS m/z (relative intensity): 424 (M⁺), 165 (100).Elementary Analysis: C₂₄H₃₂N₄OS Required: C, 67.89; H, 7.60; N, 13.20;S, 7.55. Found: C, 67.95; H, 7.66; N, 12.92; S, 7.33.

Example 7 Production of9-(oxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

In the same manner as in Example 1 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless amorphous.

IR (KBr)cm⁻¹: 3435, 3234, 2926, 1647, 1494, 1402. 1H-NMR (d₆-DMSO) δ:1.13 (12H, d, J=6.8 Hz), 1.39-1.72 (10H, m), 1.85 (2H, quint, J=7.2 Hz),2.34 (2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.2 Hz), 7.10(1H, d, J=8.6 Hz), 7.11 (1H, d, J=6.8 Hz), 7.21 (1H, dd, J=8.6, 6.8 Hz),7.30 (1H, dd, J=8.1, 5.0 Hz), 7.97 (1H, dd, J=8.1, 1.5 Hz), 8.41 (1H,dd, 5.0, 1.5 Hz),8.68 (1H, br s). EIMS m/z (relative intensity): 467(M⁺, 100). Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97;N, 8.99; S, 6.86. Found: C, 69.39; H, 8.05; N, 8.85; S, 6.56.

Example 8 Production of9-(oxazolo[4,5-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

In the same manner as in Example 6 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

Melting Point: 74-75° C. IR (KBr) cm⁻¹: 3434, 3237, 2928, 1647, 1107.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.38-1.71 (10H, m), 1.84(2H, quint, J=7.3 Hz), 2.34 (2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.38(2H, t, J=7.3 Hz), 7.11 (1H, d, J=8.3 Hz), 7.11 (1H, d, J=6.8 Hz), 7.21(1H, dd, J=8.3, 6.8 Hz), 7.64 (1H, dd, J=5.4, 0.7 Hz), 8.47 (1H, d,J=5.4 Hz), 8.68 (1H, br s), 8.88 (1H, d, 0.7 Hz). EIMS m/z (relativeintensity): 467 (M⁺), 217(100). Elementary Analysis: C₂₇H₃₇N₃O₂SRequired: C, 69.34; H, 7.97; N, 8.99; S, 6.86. Found: C, 69.28; H, 8.00;N, 8.85; S, 6.80.

Example 9 Production of9-(oxazolo[5,4-c]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

In the same manner as in Example 3 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

Melting Point: 81-82° C. IR (KBr)cm⁻¹: 3435, 3259, 2927, 1647, 1480.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=7.1 Hz), 1.39-1.69 (10H, m), 1.85(2H, quint, J=7.2 Hz), 2.34 (2H,m), 3.10 (2H, sept, J=7.1 Hz), 3.40 (2H,t, J=7.2 Hz), 7.11 (1H, d, J=8.5 Hz), 7.11 (1H, d, J=6.8 Hz), 7.21 (1H,dd, J=8.5, 6.8 Hz), 7.62 (1H, dd, J=5.1, 1.0 Hz), 8.47 (1H, d, J=5.1Hz), 8.83 (1H, br s), 8.88 (1H, d, 1.0 Hz). EIMS m/z (relativeintensity): 467 (M⁺), 217(100). Elementary Analysis: C₂₇H₃₇N₃O₂SRequired: C, 69.34; H, 7.97; N, 8.99; S, 6.86. Found: C, 69.37; H, 8.03;N, 8.85; S, 6.82.

Example 10 Production of9-(oxazolo[5,4-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

In the same manner as in Example 4 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless oil.

IR (cap) cm⁻¹: 3253, 2962, 2929, 1651, 1489, 1210. 1H-NMR (d₆-DMSO) δ:1.13 (12H, d, J=6.8 Hz), 1.38-1.69 (10H, m), 1.84 (2H, quint, J=7.1 Hz),2.34 (2H,m), 3.10 (2H, sept, J=6.8 Hz), 3.37 (2H, t, J=7.1 Hz), 7.10(1H, d, J=8.6 Hz), 7.11 (1H, d, J=6.6 Hz), 7.21 (1H, dd, J=8.6, 6.6 Hz),7.38 (1H, dd, J=7.8, 4.9 Hz), 8.00 (1H, dd, J=7.8, 1.5 Hz), 8.21 (1H,dd, 4.9, 1.5 Hz), 8.68 (1H, br s). EIMS m/z (relative intensity): 467(M⁺, 100). Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97;N, 8.99; S, 6.86. Found: C, 69.60; H, 8.20; N, 8.58; S, 6.86.

Example 11 Production of6-(5-methyloxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

10% palladium-carbon (200 mg) was added to an ethanol suspension (50 ml)of 3-hydroxy-6-methyl-2-nitropyridine (2.0 g, 13.0 mmol), with stirringin hydrogen gas atmosphere for 90 minutes. After reaction, the catalystpalladium-carbon was filtered off.

To the resulting ethanol solution of 2-amino-3-hydroxy-6-methylpyridinewas added potassium o-ethyl dithiocarbonate (4.16 g, 26.0 mmol), forheating under reflux for 17 hours to distill off the solvent. Theresidue was dissolved in water. Through addition of acetic acid, theresulting solution was adjusted to pH 5. The deposited crystal wasfiltered and washed with water, and then, the resulting crystal wasdried under heating at 80° C.

Potassium carbonate (86 mg, 0.62 mmol) and 18-crown-6 (15 mg, 0.06 mmol)were added to a solution of the resulting2-mercapto-5-methyl-oxazolo[4,5-b]pyridine (94 mg, 0.56 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (200 mg, 0.5 mmol) in DMF (4ml), and the resulting mixture was stirred at 80° C. for 4 hours. Afterthe reaction solution was diluted with water, the organic layer wasextracted with ethyl acetate. The organic layer was washed with waterand dried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (elution solvents:chloroform:methanol=20:1); theresulting crystal was recrystallized from methanol-ethyl acetate-hexane,to recover the objective compound of 150 mg (at a yield of 61%) as acolorless needle-like crystal.

Melting Point: 145-146° C. IR (KBr) cm⁻¹: 3229, 2963, 1645, 1504, 1400.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.55-1.93 (6H, m),(2H, m),2.56 (3H, s), 1.15 3.11 (2H, sept, J=6.8 Hz), 3.40 (2H, t, J=7.1 Hz),1.16 7.12 (1H, d, J=8.5 Hz), 7.12 (1H, d, J=6.6 Hz), 7.16 (1H, d, J=8.3Hz), 7.22 (1H, dd, J=8.5, 6.6 Hz), 7.84 (1H, d, J=8.3 Hz), 8.72 (1H, brs). EIMS m/z (relative intensity): 439 (M⁺), 230 (100). ElementaryAnalysis: C₂₅H₃₃N₃O₂S Required: C, 68.30; H, 7.57; N, 9.56; S, 7.29.Found: C, 68.14; H, 7.60; N, 9.45; S, 7.31.

Example 12 Production of6-(4-methyloxazolo[5,4-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 11 except for the use of2-hydroxy-4-methyl-3-nitropyridine instead of3-hydroxy-6-methyl-2-nitropyridine, reaction progressed to recover theobjective compound as a colorless crystal.

Melting Point: 157-158° C. IR (KBr) cm⁻¹: 3430, 3261, 1648, 1533. 1H-NMR(d₆-DMSO) δ: 1.13 (12H, d, J=7.1 Hz), 1.53-1.94 (6H, m), 2.38 (2H, m),2.53 (3H, s), 3.09 (2H, sept, J=7.1 Hz), 3.37 (2H, t, J=7.2 Hz), 7.08(1H, d, J=8.8 Hz), 7.09 (1H, d, J=6.6 Hz), 7.17 (1H, dd, J=4.9, 0.7 Hz),7.19 (1H, dd, J=8.8, 6.6 Hz), 8.04 (1H, d, J=4.9 Hz), 8.64 (1H, br s).EIMS m/z (relative intensity): 439 (M⁺, 100). Elementary Analysis:C₂₅H₃₃N₃O₂ S Required: C, 68.30; H, 7.57; N, 9.56; S, 7.29. Found: C,68.14; H, 7.53; N, 9.43; S, 7.26.

Example 13 Production of6-(7-methyloxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 11 except for the use of2-amino-3-hydroxy-4-methylpyridine instead of2-amino-3-hydroxy-6-methylpyridine, reaction progressed to recover theobjective compound as a colorless crystal.

Melting Point: 145-147° C. IR (KBr) cm⁻¹: 3234, 2962, 1647, 1500, 1124.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.55-1.63 (2H, m),1.70-1.79 (2H, m), 1.87-1.95 (2H, m), 2.35-2.42 (2H, m), 2.50 (3H, s),3.10 (2H, sept, J=6.8 Hz), 3.41 (2H, t, J=7.2 Hz), 7.11 (1H, d, J=7.8Hz), 7.11 (1H, d, J=7.6 Hz), 7.14 (1H, dd, J=5.1, 0.7 Hz), 7.22 (1H, dd,J=7.8, 7.6 Hz), 8.27 (1H, d, J=5.1 Hz), 8.73 (1H, br s). EIMS m/z(relative intensity): 439 (M⁺), 230 (100). Elementary Analysis:C₂₅H₃₃N₃O₂S Required: C, 68.30; H, 7.57; N, 9.56; S, 7.29. Found: C,68.13; H, 7.62; N, 9.28; S, 7.14.

Example 14 Production of6-(5,7-dimethyloxazolo[4,5-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 11 except for the use of2-amino-4,6-dimethyl-3-hydroxypyridine instead of2-amino-3-hydroxy-6-methylpyridine, reaction progressed to recover theobjective compound as a colorless crystal.

Melting Point: 169-171° C. IR (KBr) cm⁻: 3206, 2966, 1641, 1503, 1114.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.52-1.62 (2H, m),1.68-1.78 (2H, m), 1.84-1.94 (2H, m), 2.36-2.47 (2H, m), 2.48 (3H, s),2.50 (3H, s), 3.09 (2H, sept, J=6.8 Hz), 3.38 (2H, t, J=7.1 Hz), 6.99(1H, s), 7.11 (1H, d, J=7.8 Hz), 7.11 (1H, d, J=7.6 Hz), 7.21 (1H, dd,J=7.8, 7.6 Hz), 8.72 (1H, br s). EIMS m/z (relative intensity): 453(M⁺), 181 (100). Elementary Analysis: C₂₆H₃₅N₃O₂S Required: C, 68.84; H,7.78; N, 9.26; S, 7.07. Found: C, 68.95; H, 7.77; N, 9.17; S, 7.10.

Example 15 Production of6-(N-dimethylphenylsilylmethyl-N-oxazolo[4,5-b]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

Potassium carbonate (42 mg, 0.3 mmol) and 18-crown-6 (5 mg, 0.02 mmol)were added to a solution of6-(oxazolo[4,5-b]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide(78 mg, 0.19 mmol) and chloromethyldimethylphenylsilane (42 mg, 0.23mmol) in DMF (2 ml), and the resulting mixture was stirred at 80° C. for2 hours. After the reaction solution was diluted with water, the organiclayer was extracted with ether. The organic layer was washed with waterand dried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by preparative thin layerchromatography (elution solvents:hexane:acetone=5:3), to recover theobjective compound of 47 mg (at a yield of 44%) as a colorless oil.

IR (cap) cm⁻¹: 3252, 2962, 1645, 1563, 1413. 1H-NMR (d₆-DMSO) δ: 0.38(6H, s), 1.11 (12H, d, J=6.8 Hz), 1.30-1.40 (2H, m), 1.58-1.72 (4H, m),2.31 (2H, t, J=7.3 Hz), 3.07 (2H, sept, J=6.8 Hz), 3.36 (2H, s), 3.43(2H, t, J=6.8 Hz), 6.86 (1H, dd, J=7.8, 5.1 Hz), 7.09 (1H, d, J=8.3 Hz),7.09 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.30-7.35 (3H, m),7.46 (1H, dd, J=7.8, 1.5 Hz), 7.54-7.58 (2H, m), 8.05 (1H, dd, J=5.1,1.5 Hz), 8.64 (1H, br s). EIMS m/z (relative intensity): 541 (M⁺-Me),135 (100). Elementary Analysis: C₃₃H₄₄N₄O₂Si Required: C, 71.18; H,7.96; N, 10.06. Found: C, 70.94; H, 8.02; N, 10.12.

Example 16 Production of6-(N-methyl-N-oxazolo[4,5-b]pyridin-2-yl-amino)-N-(2,6-diisopropylphenyl)hexanamide

Potassium carbonate (152 mg, 1.1 mmol) and 18-crown-6 (26.4 mg, 0.1mmol) were added to a solution of the resulting6-bromo-N-(2,6-diisopropylphenyl)hexanamide (354 mmol, 1.0 mmol) andN-benzylmethylamine (121 mg, 1.0 mmol) in DMF (5 ml), and the resultingmixture was stirred at 80° C. for 2 hours. After the reaction solutionwas diluted with water, the organic layer was extracted with ether. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (20 g of silica gel;elution solvents:chloroform:methanol=30:1); the resulting crystal wasrecrystallized from acetone-ether-methanol, to recover the objectivecompound of 235 mg (at a yield of 60%) as a colorless needle-likecrystal. To a solution in ethanol (5 ml) of the benzylmethylaminoanilide(220 mg, 0.56 mmol) were added a catalytic amount of conc. hydrochloricacid (0.05 ml) and 10% palladium-carbon catalyst (100 mg), and theresulting mixture was stirred at ambient temperature in hydrogenatmosphere for 15 hours. The reaction solution was filtered throughcelite. The resulting filtrate was concentrated under reduced pressure,which was then diluted with ethyl acetate. The organic layer wassequentially washed with an aqueous saturated sodium hydrogen carbonatesolution and saturated sodium chloride solution, and was then dried overanhydrous magnesium sulfate, from which the solvents were distilled offto recover 6-methylamino-N-(2,6-diisopropylphenyl)hexanamide (145 mg ata yield of 85%) as a solid material. The methylaminoanilide (120 mg,0.39 mmol) and 2-methyloxazolo[4,5-b]pyridine (50 mg, 0.3 mmol) weremixed together and stirred at 100° C. for 3 hours. The reaction residuewas purified by silica gel column chromatography (12 g of silica gel;elution solvents:hexane:acetone=5:3). The resulting crystal wasrecrystallized from acetone-ether-hexane, to recover the objectivecompound (97 mg at a yield of 76%) as a colorless crystal.

Melting Point: 162-164° C. IR (KBr) cm⁻¹: 3435, 3230, 1656, 1562, 1412.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.40-1.50 (2H, m),1.67-1.79 (4H, m), 2.35 (2H, t, J=6.8 Hz), 3.08 (2H, sept, J=6.8 Hz),3.18 (3H, s), 3.57 (2H, t, J=7.1 Hz), 6.90 (1H, dd, J=7.8, 5.1 Hz), 7.09(1H, d, J=8.1 Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H, dd, J=8.1, 6.8 Hz),7.57 (1H, dd, J=7.8, 1.5 Hz), 8.09 (1H, dd, J=5.1, 1.5 Hz), 8.65 (1H, brs). EIMS m/z (relative intensity): 422 (M⁺), 176 (100). ElementaryAnalysis: C₂₅H₃₄N₄O₂ Required: C, 71.06; H, 8.11; N, 13.26. Found: C,71.04; H, 8.27; N, 13.05.

Example 17 Production of6-(oxazolo[4,5-b]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

2-Methylthiooxazolo[4,5-b]pyridine (65.0 mg, 0.39 mmol) and6-amino-N-(2,6-diisopropylphenyl)hexanamide (114 mg, 0.39 mmol) weremixed together and stirred at 90° C. for 2 hours. The reaction mixturewas purified by preparative thin layer chromatography (elutionsolvents:hexane:acetone=5:3). The resulting crude crystal wasrecrystallized from dichloromethane-ether-hexane, to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 152-153° C. IR (KBr) cm⁻¹: 3416, 2964, 1656, 1571, 1413.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.43-1.57 (2H, m),1.64-1.77 (4H, m), 2.35 (2H, t, J=7.3 Hz), 3.08 (2H, sept, J=6.8 Hz),3.38 (2H, dd, J=12.9, 6.8 Hz), 6.89 (1H, dd, J=7.8, 5.1 Hz), 7.09 (1H,d, J=8.3 Hz), 7.09 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.53(1H, dd, J=7.8, 1.5 Hz), 7.87 (1H, br s), 8.06 (1H, dd, J=5.1, 1.5 Hz),8.65 (1H, br s). EIMS m/z (relative intensity): 408 (M⁺, 100).Elementary Analysis: C₂₄H₃₂N₄O₂ Required: C, 70.56; H, 7.89; N, 13.71.Found: C, 70.70; H, 7.87; N, 13.51.

Example 18 Production of6-(oxazolo[4,5-c]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 17 except for the use of2-methylthiooxazolo[4,5-c]pyridine instead of2-methylthiooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 170-171° C. IR (KBr) cm⁻¹: 3258, 2966, 1648, 1578, 1465.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=7.1 Hz), 1.44-1.54 (2H, m),1.63-1.75 (4H, m), 2.35 (2H, t, J=6.8 Hz), 3.08 (2H, sept, J=7.1 Hz),3.37 (2H, dd, J=12.9, 6.8 Hz), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d,J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz), 7.31 (1H, dd, J=5.1, 0.7 Hz),7.73 (1H, br s), 8.17 (1H, d, J=5.1 Hz), 8.46 (1H, d, J=0.7 Hz), 8.67(1H, br s). EIMS m/z (relative intensity): 408 (M⁺), 162 (100).Elementary Analysis: C₂₄H₃₂N₄O₂ Required: C, 70.56; H, 7.89; N, 13.71.Found: C, 70.63; H, 7.96; N, 13.54.

Example 19 Production of6-(oxazolo[5,4-c]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 17 except for the use of2-methylthiooxazolo[5,4-c]pyridine instead of2-methylthiooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 189-190° C. IR (KBr) cm⁻¹: 3231, 2963, 1664, 1577, 1468.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.43-1.52 (2H, m),1.64-1.75 (4H, m), 2.35 (2H, t, J=6.3 Hz), 3.08 (2H, sept, J=6.8 Hz),3.38 (2H, dd, J=12.9, 6.8 Hz), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d,J=7.1 Hz), 7.18 (1H, dd, J=5.4, 0.7 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz),7.98 (1H, br s), 8.21 (1H, d, J=5.4 Hz), 8.45 (1H, d, J=0.7 Hz), 8.67(1H, br s). EIMS m/z (relative intensity): 408 (M⁺), 162 (100).Elementary Analysis: C₂₄H₃₂N₄O₂ Required: C, 70.56; H, 7.89; N, 13.71.Found: C, 70.40; H, 7.96; N, 13.55.

Example 20 Production of6-(oxazolo[5,4-b]pyridin-2-ylamino)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 17 except for the use of2-methylthiooxazolo[5,4-b]pyridine instead of2-methylthiooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 177-178° C. IR (KBr) cm⁻¹: 3232, 2962, 1660, 1585, 1404.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.45-1.54 (2H, m),1.64-1.76 (4H, m), 2.35 (2H, t, J=6.8 Hz), 3.08 (2H, sept, J=6.8 Hz),3.37 (2H, dd, J=12.9, 6.8 Hz), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d,J=6.8 Hz), 7.09 (1H, dd, J=7.6, 5.1 Hz), 7.19 (1H, dd, J=8.3, 6.8 Hz),7.48 (1H, dd, J=7.6, 0.5 Hz), 7.73 (1H, br s), 7.79 (1H, dd, J=5.1, 0.5Hz), 8.64 (1H, br s). Elementary Analysis: C₂₄H₃₂N₄O₂ Required: C,70.56; H, 7.89; N, 13.71. Found: C, 70.68; H, 7.97; N, 13.44.

Example 21 Production of6-(thiazolo[5,4-b]pyridin-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

Potassium carbonate (46 mg, 0.33 mmol) and 18-crown-6 (8 mg, 0.03 mmol)were added to a solution in DMF (2 ml) of2-mercaptothiazolo[5,4-b]pyridine (51 mmol, 0.3 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (106 mg, 0.3 mmol), and theresulting mixture was stirred at 80° C. for one hour. After the reactionsolution was diluted with water, the organic layer was extracted withethyl acetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The residue was purified by silica gel column chromatography (elutionsolvents:chloroform:methanol=50:1); the resulting crystal wasrecrystallized from acetone-ether-hexane, to recover the objectivecompound of 108 mg (at a yield of 82%) as a colorless needle-likecrystal.

Melting Point: 137-138° C. IR (KBr) cm⁻¹: 3436, 3233, 1647, 1435, 1377.1H-NMR (d₆-DMSO) d :δ 1.12 (12H, d, J=6.8 Hz), 1.52-1.60 (2H, m),1.70-1.78 (2H, m), 1.82-1.90 (2H, m), 2.37 (2H, t, J=6.8 Hz), 3.08 (2H,sept, J=6.8 Hz), 3.41 (2H, t, J=7.3 Hz), 7.10 (1H, d, J=7.6 Hz), 7.2(1H, t, J=7.6 Hz), 7.47 (1H, dd, J=8.3, 4.6 Hz), 8.14 (1H, dd, J=8.3,1.5 Hz) 8.45 (1H, dd, J=4.6, 1.5 Hz), 8.71 (1H, br s). ElementaryAnalysis: C₂₄H₃₁N₃OS₂ Required: C, 65.27; H, 7.07; N, 9.51; S, 14.52.Found: C, 65.46; H, 7.13; N, 9.33; S, 14.24.

Example 22 Production of6-(4-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

2-Nitro-3-benzyloxyphenol (334 mg, 1.36 mmol) was dissolved in aceticacid (3 ml) under heating, followed by addition of zinc (1.78 g, 27.2mmol), and the resulting mixture was stirred at ambient temperature forone hour. After the reaction solution was diluted with water, theorganic layer was extracted with ethyl acetate. The organic layer waswashed sequentially with sodium hydrogen carbonate, water and saturatedsodium chloride solution, and was dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (50 g of silica gel;elution solvents:hexane:acetone=20:3 to 5:1) and solidified fromacetone-hexane, to recover 2-amino-3-benzyloxyphenol (155 mg at a yieldof 53%) as a brown powder.

To a solution in ethanol (10 ml) of the aminophenol (135 mg, 0.627 mmol)was added potassium o-ethyl dithiocarbonate (151 mg, 0.941 mmol), andthe resulting mixture was refluxed under heating for 24 hours. After thesolution was left to stand for cooling, the solvents were distilled offunder reduced pressure; to the resulting residue was added 1 Nhydrochloric acid to adjust the solution to acidity, to extract theorganic layer. The organic layer was washed with saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off to recover a solid material. The solidmaterial was prepared as a powder by using acetone and hexane, torecover 2-mercapto-4-benzyloxybenzoxazole (143 mg at a yield of 89%).

To a solution in DMF (3 ml) of the oxazole (135 mg, 0.525 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (186 mg, 0.525 mmol) wereadded potassium carbonate (110 mg, 0.788 mmol) and 18-crown-6 (14 mg,0.053 mmol), and the resulting mixture was stirred at 80° C. for 90minutes. After the reaction solution was diluted with water, the organiclayer was extracted with ether. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (25 g of silica gel; elutionsolvents:hexane:acetone=20:3); the resulting crystal was recrystallizedfrom acetone-hexane, to recover the objective compound of 206 mg (at ayield of 74%) as a colorless crystal.

The amide (188 mg, 0.354 mmol) was dissolved in trifluoroacetic acid (5ml) while cooling in ice bath, followed by addition of thiophenol (440mg, 3.54 mmol) with stirring for 2 minutes. After the temperature wasthen back to ambient temperature, the mixture was stirred for 12 hours.Furthermore, thiophenol (440 mg, 3.54 mmol) was added to the resultingsolution, for 24-hr-stirring. Under reduced pressure, the solvents weredistilled off. The resulting residue was diluted with water andextracted with ethyl acetate. The organic layer was washed sequentiallywith saturated sodium hydrogen carbonate solution, water and saturatedsodium chloride solution, and was dried over anhydrous sodium sulfate,from which the solvents were distilled off. The residue was purified bysilica gel column chromatography (75 g of silica gel; elutionsolvents:hexane:acetone=5:1 to 10:3), and the resulting crystal wasrecrystallized from acetone-hexane, to recover the objective compound(108 mg at a yield of 69%) as a colorless crystal.

Melting Point: 160-161° C. IR (KBr) cm⁻¹: 3226, 2963, 1652, 1480, 1036,1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.50-1.91 (6H, m), 2.36(2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.33 (2H, t, J=7.1 Hz), 6.72 (1H,dd, J=8.1, 1.2 Hz), 6.97 (1H, dd, J=8.1, 1.2 Hz), 7.06 (1H, t, J=8.1Hz), 7.09 (1H, d, J=8.5 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd,J=8.5, 6.6 Hz) 8.66 (1H, br s), 9.57 (1H, br s). EIMS m/z (relativeintensity): 440 (M⁺, 100). Elementary Analysis: C₂₅H₃₂N₂O₃S Required: C,68.15; H, 7.32; N, 6.36; S, 7.28. Found: C, 68.05; H, 7.33; N, 6.34; S,7.18.

Example 23 Production of6-(4-acetyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

Acetic anhydride (18 mg, 0.177 mmol) was added to a solution of6-(4-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (52mg, 0.118 mmol) in pyridine (1 ml), with stirring at ambient temperaturefor 12 hours. The reaction solution was diluted with an aqueous 5%potassium hydrogen sulfate solution, was extracted the organic layerwith ether. The organic layer was washed sequentially with an aqueous 5%potassium hydrogen sulfate solution, water and saturated sodium chloridesolution, and was dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (5 g of silica gel; elutionsolvents:hexane:acetone=5:1), and the resulting crystal wasrecrystallized from acetone-hexane, to recover the objective compound(37 mg at a yield of 64%) as a colorless crystal.

Melting Point: 116-117° C. IR (KBr) cm⁻¹: 3436, 3222, 2962, 1772, 1645.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.50-1.91 (6H, m), 2.32(3H, s), 2.36 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t, J=7.1Hz), 7.08 (1H, dd, J=8.1, 1.0 Hz), 7.09 (1H, d, J=8.6 Hz), 7.09 (1H, d,J=6.6 Hz), 7.20 (1H, dd, J=8.6, 6.6 Hz), 7.29 (1H, t, J=8.1 Hz), 7.46(1H, dd, J=8.1, 1.0 Hz), 8.67 (1H, br.s), EIMS m/z (relative intensity):482 (M⁺, 100). Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H,7.10; N, 5.80; S, 6.64. Found: C, 67.19; H, 7.18; N, 5.82; S, 6.55.

Example 24 Production of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

p-Toluenesulfonic acid monohydrate (95 mg, 0.5 mmol) was added to asolution of 3-hydroxyanthranilic acid (1.93 g, 12.6 mmol) inhydrochloric acid-saturated methanol (40 ml) solution, for reflux underheating for 12 hours. The solvents were distilled off, and the resultingresidue was diluted with ethyl acetate. The organic layer was washedsequentially with an aqueous potassium hydrogen carbonate solution,water and saturated sodium chloride solution, and was dried overanhydrous sodium sulfate, from which the solvents were distilled off.The residue was dissolved in ether, and then, insoluble matters werefiltered off. The filtrate was concentrated to recover the residue.Triethylamine (1.85 g, 18.25 mmol) was added to a solution of theresidue (1.22 g, 7.37 mmol) in dichloromethane (10 ml), followed bydropwise addition of a solution of thiophosgene (923 mg, 8.03 mmol) indichloromethane (2 ml), for subsequent stirring at ambient temperaturefor 5 minutes. The reaction solution was concentrated, and the resultingresidue was diluted with ethyl acetate. The organic layer was washedsequentially with 1 N hydrochloric acid, water and saturated sodiumchloride solution, and was dried over anhydrous sodium sulfate, fromwhich the solvents were distilled off. The resulting solid matter wascrystallized from ethyl acetate-hexane, to recover4-methoxycarbonyl-2-mercaptobenzoxazole (1.28 g at a yield of 84%). To asolution in DMF (20 ml) of the oxazole (1.05 g, 5.0 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (1.77 g, 5.0 mmol) wereadded potassium carbonate (1.04 g, 7.5 mmol) and 18-crown-6 (132 mg, 0.5mmol), and the resulting mixture was stirred at 80° C. for 2 hours.After the reaction solution was diluted with water, the organic layerwas extracted with ether. The organic layer was washed sequentially withwater and saturated sodium chloride solution, and was dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The residue was purified by silica gel column chromatography (100 g ofsilica gel; elution solvents:hexane:acetone=5:1); the resulting crystalwas recrystallized from acetone-hexane, to recover the objectivecompound of 1.84 g (at a yield of 76%) as a colorless needle-likecrystal.

Melting Point: 131-132° C. IR (KBr) cm⁻¹: 3408, 3221, 3172, 2965, 1713,1641. 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.53-1.97 (6H, m),2.39 (2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.40 (2H, t, J=7.2 Hz), 3.91(3H, s), 7.08 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd,J=8.8, 6.6 Hz), 7.34 (1H, t, J=8.1 Hz), 7.74 (1H, dd, J=8.1, 1.2 Hz),7.82 (1H, dd, J=8.1, 1.2 Hz), 8.60 (1H, br s). EIMS m/z (relativeintensity): 482 (M⁺), 176 (100). Elementary Analysis: C₂₇H₃₄N₂O₄SRequired: C, 67.19; H, 7.10; N 5.80; S, 6.64. Found: C, 67.29; H, 7.21;N, 5.71; S, 6.62.

Example 25 Production of6-(4-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution in THF (10 ml) of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(965 mg, 2.0 mmol) was added t-BuOH (4 ml), followed by addition of asolution of lithium hydroxide monohydrate (336 mg, 8 mmol) in water (4ml), with stirring at ambient temperature for 12 hours. Afterdistillation of the solvents under reduced pressure, the resultingresidue was extracted with ethyl acetate. The organic layer was washedsequentially with 0.5 N hydrochloric acid, water and saturated sodiumchloride solution, and was dried over anhydrous sodium sulfate, fromwhich the solvents were distilled off. The resulting crude crystal wasrecrystallized from acetone-hexane, to recover the objective compound(799 mg at a yield of 85%) as a colorless crystal.

Melting Point: 174-176° C. IR (KBr) cm⁻¹: 3421, 3244, 2963, 1649, 1493.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.47-1.88 (6H, m), 2.37(2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t, J=7.1 Hz), 7.08 (1H, d,J=8.5 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd, J=8.5, 6.6 Hz), 7.34(1H, t, J=7.9 Hz), 7.74(1H, dd, J=7.9,0.5 Hz), 7.80 (1H, dd, J=7.9,0.5Hz), 8.76 (1H, br s). Elementary Analysis: C₂₃H₃₂N₂O₄S Required: C,66.64; H, 6.88; N, 5.98; S, 6.84. Found: C, 66.36; H, 6.86; N, 6.03; S,6.64.

Example 26 Production of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution in THF (10 ml) of6-(4-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(613 mg, 1.5 mmol) was added triethylamine (200 mg, 1.98 mmol), followedby gradual addition of methyl chloroformate (195 mg, 1.80 mmol) undercooling in ice bath, with stirring for 30 minutes. The depositedtriethylamine hydrochloride salt was filtered off; to the resultingfiltrate under cooling in ice bath was gradually added an aqueoussuspension (1.5 m) of sodium borohydride (227 mg, 6.0 mmol); and theresulting mixture was stirred for 30 minutes. To the reaction solutionwas added water, to extract the organic layer with ethyl acetate. Theorganic layer was washed sequentially with water and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (25 g of silica gel; elutionsolvents:hexane:acetone=5:2 to 5:3), and the resulting crude crystal wasrecrystallized from acetone-ether-hexane, to recover the objectivecompound (468 mg at a yield of 69%) as a colorless crystal.

Melting Point: 93-95° C. IR (KBr) cm⁻¹: 3358, 3243, 2963, 1646, 1506.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.50-1.92 (6H,m), 2.37 (2H,m), 3.09 (2H, sept, J=6.8 Hz), 3.35 (2H, t, J=7.1 Hz), 4.67 (1H, t,J=5.5 Hz),4.83 (2H, d, J=5.5 Hz), 7.09 (1H, d, J=8.1 Hz), 7.09 (1H, d,J=6.6 Hz), 7.19 (1H, dd, J=8.1, 6.6 Hz), 7.24 (1H, t, J=7.8 Hz), 7.37(1H, dd, J=7.8, 1.4 Hz), 7.40 (1H, dd, J=7.8, 1.4 Hz), 8.66 (1H, br s).EIMS m/z (relative intensity): 454 (M⁺), 204 (100). Elementary Analysis:C₂₆H₃₄N₂O₃S Required: C, 68.69; H, 7.54; N, 6.16; S, 7.05. Found: C,68.70; H, 7.57; N, 6.15; S, 7.01.

Example 27 Production of6-[4-(N,N-dimethylaminomethyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

To a solution in THF (5 ml) of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(182 mg, 0.4 mmol) were added triethylamine (81 mg, 0.8 mmol) and4-dimethylaminopyridine (9.8 mg, 0.08 mmol), followed by dropwiseaddition of methane sulfonylchloride (64 mg, 0.56 mmol) under cooling inice bath with stirring, and the resulting mixture was stirred for 30minutes. The reaction solution was extracted with ethyl acetate; theorganic layer was washed sequentially with 0.5 N hydrochloric acid,water and saturated sodium chloride solution and dried over anhydroussodium sulfate, from which the solvents were distilled off. To asolution in THF (7 ml) of the resulting residue (209 mg) was added anaqueous 40% N,N-dimethylamine solution (180 mg, 1.6 mmol), for refluxunder heating for one hour. After the reaction solution was left tostand and cooled, the reaction solution was extracted with ethylacetate; the organic layer was washed with an aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride solution anddried over anhydrous sodium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (10 g of silica gel; elution solvents:hexane:acetone=5:3,chloroform:ammonia-saturated methanol=19:1), and the resulting crystalwas recrystallized from acetone-hexane, to recover the objectivecompound (137 mg at a yield of 71%) as a colorless crystal.

Melting Point: 113-115° C. IR (KBr) cm⁻¹: 3435, 3237, 2964, 1647, 1506.H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.93 (6H,m), 2.24 (6H,s), 2.37 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.35 (2H, t, J=7.2 Hz),3.77 (2H, s), 7.09 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H,dd, J=8.3, 6.8Hz), 7.22 (1H, t, J=7.6 Hz), 7.28 (1H, dd, J=7.6, 1.7 Hz),7.41 (1H, dd, J=7.6, 1.7 Hz), 8.65 (1H, br s). EIMS m/z (relativeintensity): 481 (M⁺), 207 (100) Elementary Analysis: C₂₈H₃₉N₃O₂SRequired: C, 69.82; H, 8.16; N, 8.72; S, 6.66. Found: C, 69.76; H, 8.23;N, 8.64; S, 6.72.

Example 28 Production of6-(4-N,N-dimethylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution in THF (50 ml) of 2-amino-3-nitrophenol (1.54 g, 10 mmol)was added portions of sodium hydride (528 mg, 22 mmol) under cooling inice bath, and the resulting mixture was stirred at 60° C. for 5 minutes.Then, portions of thiophosgene (1.38 g, 12 mmol) were added to themixture, which was then stirred at 60° C. for 5 minutes. Afterdistillation of the solvent, the resulting residue was adjusted toacidity by using 1 N hydrochloric acid; the resulting solid matter wasfiltered and recovered, which was then purified by silica gel columnchromatography (200 g of silica gel; elution solvents: chloroform,chloroform:methanol=100:1 to 50:1), and the resulting solid matter wascrystallized from acetone-hexane, to recover2-mercapto-4-nitrobenzoxazole (807 mg at a yield of 41%) as a yellowcrystal. To a solution in DMF (6 ml) of the resulting oxazole (216 mg,1.1 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (390 mg, 1.1mmol) were added potassium carbonate (228 mg, 1.65 mmol) and 18-crown-6(29 mg, 0.11 mmol), and the resulting mixture was stirred at 80° C. for2 hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (70 g of silica gel; elution solvents:hexane:acetone=5:1to 10:3); the resulting crystal was recrystallized from acetone-hexane,to recover6-(4-nitrobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (304mg at a yield of 59%) as a pale yellow crystal (melting point of132-133° C.).

The nitro material (386 mg, 0.822 mmol) was dissolved in acetic acid (8ml), followed by addition of zinc (1.07 g, 16.44 mmol) under cooling inice bath, and the resulting mixture was stirred at ambient temperaturefor 5 minutes. The reaction solution was diluted with ethyl acetate andfiltered through celite, which was then adjusted to neutrality by usingan aqueous sodium hydrogen carbonate solution. The organic layer waswashed sequentially with an aqueous sodium hydrogen carbonate solution,water and saturated sodium chloride solution, and was dried overanhydrous sodium sulfate, from which the solvents were distilled off.The residue was purified by silica gel column chromatography (38 g ofsilica gel; elution solvents:dichloromethane:hexane:acetone=4:4:1); theresulting crystal was recrystallized from acetone-hexane, to recover6-(4-aminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (231mg at a yield of 64%) as a pale yellow crystal (melting point of167-168° C.). To a solution of the amine material (273 mg, 0.621 mmol)in acetonitrile (7.5 ml) were sequentially added a solution of anaqueous 37% formaldehyde solution (504 mg, 5.78 mmol) in acetonitrile(7.5 ml) and a suspension of sodium cyanoborohydride (156 mg, 2.48 mmol)in acetonitrile (1 ml); and acetic acid (48 μl) was added to theresulting mixture with stirring at ambient temperature. The resultingmixture was further stirred for 30 minutes as it was. After distillationof the solvents, the resulting residue was diluted with water, andextracted with ethyl acetate. The organic layer was sequentially washedwith water and saturated sodium chloride solution and dried overanhydrous sodium sulfate, from which the solvents were distilled off.The residue was purified by preparative thin layer chromatography(elution solvents:hexane:acetone=5:2); the resulting crystal wasrecrystallized from acetone-hexane, to recover the objective compound(177 mg at a yield of 61%) as a colorless crystal.

Melting Point: 129-130° C. IR (KBr) cm⁻¹: 3435, 3226, 2967, 1645, 1524.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=7.1 Hz), 1.51-1.92 (6H, m), 2.36(2H, m), 3.09 (2H, sept, J=7.1 Hz), 3.16 (6H, s), 3.30 (2H, t, J=7.1Hz), 6.49 (1H, dd, J=8.8, 0.7 Hz), 6.84 (1H, dd, 8.1, 0.7 Hz), 7.07 (1H,d, J=8.1 Hz), 7.08 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=6.4 Hz), 7.19 (1H,dd, J=8.6, 6.4 Hz), 8.63 (1H, br s). EIMS m/z (relative intensity): 467(M⁺, 100) Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97;N, 8.99; S, 6.86. Found: C, 69.42; H, 8.10; N, 8.85; S, 6.77.

Example 29 Production of6-(5-benzyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution in acetatic acid (21 ml) of 4-benzyloxy-2-nitrophenol(1.67 g, 6.8mmol) was added zinc (8.89 g, 136 mmol) under cooling in icebath, with stirring at ambient temperature for 2 hours. Zinc wasfiltered off by using celite; the filtrate was adjusted to neutralitywith sodium hydrogen carbonate, and extracted with ethyl acetate. Theorganic layer was sequentially washed with an aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride solution anddried over anhydrous sodium sulfate, from which the solvents weredistilled off to recover 4-benzyloxy-2-aminophenol (1.40 g at a yield of95%) as a brown oil. To a solution of the aminophenol (1.4 g, 6.5 mmol)in ethanol (35 ml) was added potassium o-ethyl dithiocarbonate (1.34 g,8.36 mmol), for reflux under heating for 24 hours. After the reactionsolution was left to stand for cooling, the solvents were distilled off;the resulting residue was dissolved in water and adjusted to acidity byusing conc. hydrochloric acid, and extracted with ethyl acetate. Theorganic layer was washed with saturated sodium chloride solution anddried over anhydrous sodium sulfate, from which the solvents weredistilled off. The resulting solid material was crystallized fromacetone-hexane, to recover 2-mercapto-5-benzyloxybenzoxazole (1.27 g ata yield of 71%) as a pale pink crystal. To a solution of the oxazole(514 mg, 2.0 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (708mg, 2.0 mmol) in DMF (5 ml) were added potassium carbonate (345 mg, 2.5mmol) and 18-crown-6 (65 mg, 0.24 mmol), and the resulting mixture wasstirred at 80° C. for 3 hours. After the reaction solution was dilutedwith water, the organic layer was extracted with ethyl acetate. Theorganic layer was washed sequentially with water and saturated sodiumchloride solution, and was dried over anhydrous magnesium sulfate, fromwhich the solvents were distilled off. The residue was purified bysilica gel column chromatography (50 g of silica gel; elutionsolvents:hexane:acetone=5:1 to 10:3); the resulting crystal wasrecrystallized from acetone-hexane, to recover the objective compound(734 mg at a yield of 69%) as a pale red crystal.

Melting Point: 102-104° C. IR (KBr) cm⁻¹: 3413, 3243, 2964, 1644, 1496.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.46-1.92 (6H, m), 2.47(2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.33 (2H, t, J=7.1 Hz), 5.13 (2H,s), 6.94 (1H, dd, J=8.8, 2.4 Hz), 7.08 (1H, d, 8.8 Hz), 7.09 (1H, d,J=6.8 Hz), 7.19 (1H, dd, J=8.8, 6.8 Hz), 7.21 (1H, d, J=2.4 Hz),7.25-7.47 (6H, m), 8.68 (1H, br s). EIMS m/z (relative intensity): 530(M⁺, 100). Elementary Analysis: C₃₂H₃₈N₂O₃S Required: C, 72.42; H, 7.22;N, 5.28; S, 6.04. Found: C, 72.41; H, 7.24; N, 5.11; S, 5.82.

Example 30 Production of6-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

Under cooling in ice bath,6-(5-benzyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(514 mg, 2.0 mmol) was dissolved in trifluoroacetic acid (20 ml),followed by addition of thioanisole (1.24 g, 10 mmol), with stirring atambient temperature for 12 hours. The solvent was distilled off from thereaction solution; the resulting residue was diluted with water, andextracted with ethyl acetate. The organic layer was washed sequentiallywith a saturated sodium hydrogen carbonate solution and saturated sodiumchloride solution, and was dried over anhydrous magnesium sulfate, fromwhich the solvents were distilled off. The residue was purified bysilica gel column chromatography (30 g of silica gel; elutionsolvents:hexane:acetone=5:1 to 5:2), to recover the objective compound(459 mg at a yield of 97%) as a pale red amorphous. IR (KBr) cm⁻¹: 3247,2963, 1649, 1445, 1153. 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz),1.48-1.91 (6H, m), 2.35 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.31 (2H, t,J=7.1 Hz), 6.70 (1H, dd, J=8.8, 2.4 Hz), 6.92 (1H, d, J=2.4 Hz), 7.09(1H, d, J=8.3 Hz), 7.10 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.3, 7.1 Hz),7.31 (1H, d, J=8.8 Hz), 8.68 (1H, br s), 8.92 (1H, s). EIMS m/z(relative intensity): 440 (M⁺, 100). Elementary Analysis: C₂₅H₃₂N₂O₃SRequired: C, 68.15; H, 7.32; N, 6.36; S, 7.28. Found: C, 68.16; H, 7.45;N, 6.26; S, 6.86.

Example 31 Production of9-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

To a solution of 2-mercapto-5-benzyloxybenzoxazole (515 mg, 2.0 mmol)and 9-bromo-N-(2,6-diisopropylphenyl)nonanamide (793 mg, 2.0 mmol) inDMF (15 ml) were added potassium carbonate (415 mg, 3.0 mmol) and18-crown-6 (53 mg, 0.02 mmol), and the resulting mixture was stirred at80° C. for one hour. After the reaction solution was diluted with water,the organic layer was extracted with ethyl acetate. The organic layerwas washed sequentially with water and saturated sodium chloridesolution, and was dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (75 g of silica gel; elutionsolvents:hexane:acetone=5:1); the resulting crystal was recrystallizedfrom acetone-hexane, to recover the objective compound (990 mg at ayield of 86%) as a colorless crystal.

Under cooling in ice bath,9-[5-benzyloxybenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)nonanamide(859 mg, 1.5 mmol) was dissolved in trifluoroacetic acid (40 ml),followed by addition of thiophenol (1.86 g, 15 mmol), with stirring atambient temperature for 24 hours. The solvent was distilled off underreduced pressure; the resulting residue was diluted with water, andextracted with ethyl acetate. The organic layer was washed sequentiallywith saturated sodium hydrogen carbonate solution, water and saturatedsodium chloride solution, and was dried over anhydrous sodium sulfate,from which the solvents were distilled off. The residue was purified bysilica gel column chromatography (85 g of silica gel; elutionsolvents:hexane:acetone=5:1 to 10:3 to 5:2), to recover the objectivecompound (634 mg at a yield of 88%) as a pale pink amorphous.

IR (KBr) cm⁻¹: 3250, 2929, 1651, 1447, 1154. 1H-NMR (d₆-DMSO) δ: 1.13(12H, d, J=6.8 Hz), 1.37-1.69 (10H, m), 1.80 (2H, quint, J=7.2 Hz) 2.34(2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.30 (2H, t, J=7.2 Hz), 6.72 (1H,dd, J=8.8, 2.0 Hz), 6.94 (1H, dd, J=2.0, 0.5 Hz), 7.10 (1H, d, J=8.6Hz), 7.11 (1H, d, J=6.6 Hz), 7.21 (1H, dd, J=8.6, 6.6 Hz), 7.32 (1H, dd,J=8.8, 0.5 Hz) 8.87 (1H, br s), 8.93 (1H, br s). EIMS m/z (relativeintensity): 482 (M⁺, 100). Elementary Analysis: C₂₈H₃₈N₂O₃S Required: C,69.68; H, 7.93; N, 5.80; S, 6.64. Found: C, 69.41; H, 8.12; N, 5.62; S,6.92.

Example 32 Production of6-(5-acetylthiobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 22 except for the use of6-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of 6-(4-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as apale red crystal.

Melting Point: 102-104° C. IR (KBr) cm⁻¹: 3247, 2963, 1649, 1445, 1153.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.51-1.96 (6H, m), 2.28(3H, S), 2.38 (2H, m), 3.11 (2H, sept, J=6.8 Hz), 3.38 (2H, t, J=7.1Hz), 7.06 (1H, dd, J=8.6, 2.4 Hz), 7.11 (1H, d, J=8.8 Hz), 7.12 (1H, d,7.1 Hz), 7.23 (1H, dd, J=8.8, 7.1 Hz), 7.59 (1H, d, J=8.6 Hz), 8.71 (1H,br s). EIMS m/z (relative intensity): 482 (M⁺, 100). ElementaryAnalysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H, 7.10; N, 5.80; S, 6.64.Found: C, 67.40; H, 7.20; N, 5.72; S, 6.50.

Example 33 Production of9-(5-acetyloxythiobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

In the same manner as in Example 22 except for the use of9-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamideinstead of6-(4-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

Melting Point: 89-90° C. IR (KBr) cm⁻¹: 3433, 3266, 1770, 1649, 1496.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.37-1.71 (10H, m), 1.82(2H, quint, J=7.2 Hz), 2.25 (3H, S), 2.33 (2H, m), 3.09 (2H, sept, J=6.8Hz), 3.32 (2H, t, J=7.2 Hz), 7.01 (1H, dd, J=8.8, 2.4 Hz), 7.08 (1H, d,J=8.6 Hz), 7.09 (1H, d, J=7.1 Hz), 7.19 (1H, dd, J=8.6, 7.1 Hz), 7.33(1H, dd, J=2.4, 0.5 Hz), 7.52 (1H, dd, J=8.8, 0.5 Hz), 8.61 (1H, br s)EIMS m/z (relative intensity): 524 (M⁺, 100). Elementary Analysis:C₃₀H₄₀N₂O₄S Required: C, 68.68; H, 7.68; N, 5.34; S, 6.11. Found: C,68.79; H, 7.79; N, 5.31; S, 6.09.

Example 34 Production of6-(5-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 24 except for the use of3-amino-4-hydroxybenzoic acid instead of 3-hydroxyanthranilic acid,reaction progressed to recover the objective compound as a colorlessneedle-like crystal.

Melting Point: 104-106° C. IR (KBr) cm⁻¹: 3417, 3251, 2960, 1720, 1651.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.47-1.95 (6H, m), 2.36(2H,m), 3.07 (2H, sept, J=6.8 Hz), 3.38 (2H, t, J=7.1 Hz), 3.88 (3H, S),7.08 (1H, d, J=8.5 Hz), 7.09 (1H, d, J=7.1 Hz), 7.20 (1H, dd, J=8.5, 7.1Hz), 7.67 (1H, d, J=8.3 Hz), 7.93 (1H, dd, J=8.5, 2.4 Hz), 8.12 (1H, dd,J=2.4 Hz), 8.68 (1H, br s). Elementary Analysis: C₂₇H₃₄N₂O₄S Required:C, 67.19; H, 7.10; N, 5.80; S, 6.64. Found: C, 67.32; H, 7.11; N, 5.81;S, 6.62.

Example 35 Production of6-(5-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 25 except for the use of6-(5-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

Melting Point: 198-200° C. IR (KBr) cm⁻¹: 3610, 3236, 2963, 1691, 1646.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.53-1.94 (6H, m), 2.38(2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.37 (2H, t, J=7.2 Hz), 7.08 (1H, d,J=8.5 Hz),7.09 (1H, d, J=6.6 Hz), 7.19 (1H,dd, J=8.5, 6.6 Hz), 7.58 (1H,dd, J=8.5, 0.5 Hz), 7.93 (1H, dd, J=8.5, 1.7 Hz), 8.12 (1H, dd, J=1.7,0.5 Hz), 8.62 (1H, br s). EIMS m/z (relative intensity): 468 (M⁺),176(100) Elementary Analysis: C₂₆H₃₂N₂O₄S Required: C, 66.64; H, 6.88;N, 5.98; S, 6.84. Found: C, 66.78; H, 7.00; N, 5.98; S, 6.67.

Example 36 Production of6-(5-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 26 except for the use of6-(5-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

Melting Point: 152-153° C. IR (KBr) cm⁻¹: 3432, 3222, 2965, 1646, 1491.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.50-1.92 (6H,m), 2.36 (2H,m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t, J=7.1 Hz), 4.59 (2H, s),7.09 (1H, d, J=8.1 Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H, dd, J=8.1 ,6.8Hz), 7.24 (1H, dd, J=8.3, 1.5 Hz), 7.46 (1H, d, J=8.3 Hz), 7.52 (1H,d, J=1.5 Hz), 8.67 (1H, br s). EIMS m/z (relative intensity): 454 (M⁺),176 (100) Elementary Analysis: C₂₆H₃₄N₂O₃S Required: C, 68.69; H, 7.54;N, 6.16; S, 7.05. Found: C, 68.59; H, 7.58; N, 6.12; S, 7.11.

Example 37 Production of6-[5-(N,N-dimethylaminomethyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 27 except for the use of6-(5-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as acolorless crystal.

Melting Point: 112-113° C. IR (KBr) cm⁻¹: 3429, 3238, 2961, 1652, 1502.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.50-1.92 (6H,m),2.19 (3H,s), 2.20 (3H, s), 2.36 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t,J=7.2 Hz), 3.49 (2H, s), 7.09 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=7.1 Hz),7.19 (1H, dd, J=8.6, 7.1 Hz), 7.21 (1H, dd, J=8.6, 1.5 Hz), 7.46 (1H, d,J=8.6 Hz), 7.48 (1H, d, J=1.5 Hz), 8.66 (1H, br s). EIMS m/z (relativeintensity): 481 (M⁺), 207 (100). Elementary Analysis: C₂₈H₃₉N₃O₂SRequired: C, 69.82; H, 8.16; N, 8.72; S, 6.66. Found: C, 69.65; H, 8.18;N, 8.65; S, 6.54.

Example 38 Production of6-(5-N,N-dimethylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 2-amino-4-nitrophenol (1.54 g, 10 mmol) in ethanol (50ml) was added potassium o-ethyl dithiocarbonate (1.76 g, 11 mmol), atreflux under heating for 12 hours. After the reaction solution was leftto stand for cooling, the solvents were distilled off under reducedpressure; the resulting residue was adjusted to acidity by using 1 Nhydrochloric acid, and extracted with ethyl acetate. The organic layerwas washed with saturated sodium chloride solution and dried overanhydrous sodium sulfate, from which the solvents were distilled off.The resulting solid material was crystallized from acetone-hexane, torecover 2-mercapto-5-nitrobenzoxazole (1.90 g at a yield of 97%) as ayellow crystal. To a solution of the oxazole (392 mg, 2.0 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (708 mg, 2.0 mmol) in DMF (5ml) were added potassium carbonate (304 mg, 2.2 mmol) and 18-crown-6 (53mg, 0.2 mmol), and the resulting mixture was stirred at 80° C. for 3hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (50 g of silica gel; elution solvents:hexane:acetone=5:1to 10:3); the resulting crystal was recrystallized from acetone-hexane,to recover6-(5-nitrobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (796mg at a yield of 85%) as a pale yellow crystal (of a melting point of118 to 119° C.). The nitro material (670 mg, 1.42 mmol) was dissolved inacetic acid (15 ml), followed by addition of zinc (1.86 g, 28.5 mmol)under cooling in ice bath, and the resulting mixture was stirred atambient temperature for 2 hours. After the reaction solution wasfiltered through celite, the filtrate was adjusted to neutrality byusing an aqueous saturated sodium hydrogen carbonate solution, andextracted with ethyl acetate. The organic layer was washed sequentiallywith an aqueous sodium hydrogen carbonate solution, water and saturatedsodium chloride solution, and was dried over anhydrous sodium sulfate,from which the solvents were distilled off. The residue was purified bysilica gel column chromatography (12 g of silica gel; elutionsolvents:chloroform:methanol=97:3); the resulting crystal wasrecrystallized from methylene chloride-ether, to recover6-(5-aminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (374mg at a yield of 60%) as a pale yellow crystal (of a melting point of151-152° C.). To a solution of the aniline (220 mg, 0.50 mmol) inacetonitrile (3 ml) were sequentially added an aqueous 37% formaldehydesolution (406 mg, 5.0 mmol) and a suspension of sodium cyanoborohydride(126 mg, 2.0 mmol) in acetonitrile (2 ml), followed by dropwise additionof acetic acid (45 μl) with stirring at ambient temperature; and then,the resulting mixture was further stirred for 30 minutes. Afterdistillation of the solvents, the resulting residue was diluted withwater, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solutionand dried over anhydrous sodium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (10 g of silica gel; elution solvents:hexane:methylenechloride:acetone=4:4:1), and the resulting crystal was recrystallizedfrom ether-hexane, to recover the objective compound (122 mg at a yieldof 52%) as a colorless needle-like crystal.

Melting Point: 130-132° C. IR (KBr) cm⁻¹: 3435, 3227, 2961, 1651, 1494.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.47-1.92 (6H, m), 2.35(2H,m), 2.89 (6H, s), 3.08 (2H, sept, J=6.8 Hz), 3.31 (2H, t, J=7.1 Hz),6.71 (1H, dd, J=8.8, 2.4 Hz), 6.87 (1H, d, J=2.4 Hz), 7.08 (1H, d, J=8.3Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H, dd, J=8.3, 6.8 Hz), 7.33 (1H, d,J=8.8 Hz), 8.68 (1H, br s). EIMS m/z (relative intensity): 467 (M⁺,100). Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.82. Found: C, 69.44; H, 7.97; N, 8.94; S, 6.86.

Example 39 Production of6-(6-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 2-mercapto-6-hydroxybenzoxazole (167 mg, 1.0 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (354 mg, 1.0 mmol) in DMF (6ml) were added potassium carbonate (207 mg, 1.5 mmol) and 18-crown-6 (26mg, 0.01 mmol), and the resulting mixture was stirred at 80° C. for 2hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous sodium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (70 g of silica gel; elution solvents:hexane:acetone=10:3to 5:1), to recover the objective compound (347 mg at a yield of 79%) asa pale brown amorphous.

IR (KBr) cm⁻¹: 3247, 2963, 1652, 1484. 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d,J=6.8 Hz), 1.51-1.91 (6H, m), 2.37 (2H, m), 3.10 (2H, sept, J=6.8 Hz),3.28 (2H, t, J=7.2 Hz), 6.75 (1H, dd, J=8.5, 2.2 Hz), 6.91 (1H, d, J=2.2Hz), 7.08 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd,J=8.8, 6.6 Hz), 7.31 (1H, d, J=8.5 Hz) 8.61 (1H, br s), 9.08 (1H, br s).EIMS m/z (relative intensity): 440 (M⁺, 100). Elementary Analysis:C₂₅H₃₂N₂O₃S Required: C, 68.15; H, 7.32; N, 6.36; S, 7.28. Found: C,67.93; H, 7.37; N, 6.31; S, 7.03.

Example 40 Production of6-(6-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 24 except for the use of4-amino-3-hydroxybenzoic acid instead of 3-hydroxyanthranilic acid,reaction progressed to recover the objective compound as a colorlessneedle-like crystal.

Melting Point: 157-158° C. IR (KBr) cm⁻¹: 3412, 3236, 2959, 1714, 1647.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.51-1.94 (6H, m), 2.37(2H,m), 3.09 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.2 Hz), 3.88 (3H, s),7.08 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=6.6 Hz), 7.20 (1H, dd, J=8.6, 6.6Hz), 7.65 (1H, dd, J=8.3, 0.5 Hz), 7.95 (1H, dd, J=8.3, 1.7 Hz), 8.09(1H, dd, J=1.7, 0.5 Hz), 8.67 (1H, br s). EIMS m/z (relative intensity):483 (M⁺+1), 69 (100). Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C,67.19; H, 7.10; N, 5.80; S, 6.64. Found: C, 67.35; H, 7.13; N, 5.78; S,6.47.

Example 41 Production of6-(6-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 25 except for the use of6-(6-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

Melting Point: 212-213° C. IR (KBr) cm⁻¹: 3216, 2964, 1648, 1491, 1430.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.51-1.94 (6H, m), 2.37(2H,m), 3.09 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.1 Hz), 7.08 (1H, d,J=8.5 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H,dd, J=8.5, 6.6 Hz), 7.62(1H, dd, J=8.3, 0.4 Hz), 7.94 (1H, dd, J=8.3, 1.5 Hz), 8.06 (1H, dd,J=1.5, 0.4 Hz), 8.65 (1H, br s). EIMS m/z (relative intensity): 468(M⁺), 176 (100). Elementary Analysis: C₂₆H₃₂N₂O₄S Required: C, 66.64; H,6.88; N, 5.98; S, 6.84. Found: C, 66.81; H, 7.00; N, 5.96; S, 6.64.

Example 42 Production of6-(6-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 26 except for the use of6-(6-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

Melting Point: 93-95° C. IR (KBr) cm⁻¹: 3421, 3261, 2964, 1645, 1492.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.50-1.92 (6H, m), 2.37(2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.34 (2H, t, J=7.2 Hz), 4.61 (2H,s), 7.09 (1H, d, J=8.6 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd, J=8.6, 6.6Hz), 7.26 (1H, dd, J=8.1, 1.3 Hz), 7.49 (1H, dd, J=8.1, 0.7 Hz),7.49 (1H, dd, J=1.3, 0.7 Hz), 8.64 (1H, br s). EIMS m/z (relativeintensity): 454 (M⁺), 69 (100). Elementary Analysis: C₂₆H₃₄N₂O₃SRequired: C, 68.69; H, 7.54; N, 6.16; S, 7.05. Found: C, 68.52; H, 7.50;N, 6.12; S, 7.09.

Example 43 Production of6-[6-(N,N-dimethylaminomethyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 27 except for the use of6-(6-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as acolorless crystal.

Melting Point: 82-84° C. IR (KBr) cm⁻¹: 3246, 2963, 1652, 1503, 1220.H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.46-1.93 (6H, m), 2.24 (6H,s), 2.36 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.34 (2H, t, J=7.3 Hz),3.58 (2H, s), 7.08 (1H, d, J=8.3 Hz), 7.09 (1H, d, J=6.6 Hz), 7.20 (1H,dd, J=8.3, 6.6 Hz), 7.25 (1H, dd, J=8.1, 1.2 Hz), 7.49 (1H, d, J=1.2Hz), 7.51 (1H, d, J=8.1 Hz), 8.66 (1H, br s). Elementary Analysis:C₂₈H₃₉N₃O₂S.0.5H₂O Required: C, 68.53; H, 8.22; N, 8.56; S, 6.53. Found:C, 68.53; H, 8.14; N, 8.44; S, 6.64.

Example 44 Production of6-(6-N,N-dimethylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 28 except for the use of2-amino-6-nitrophenol instead of 2-amino-3-nitrophenol, reactionprogressed to recover the objective compound as a colorless needle-likecrystal.

Melting Point: 149-150° C. IR (KBr) cm⁻¹: 3435, 3231, 2966, 1650, 1100.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.48-1.89 (6H, m), 2.36(2H,m), 2.93 (6H, s), 3.09 (2H, sept, J=6.8 Hz), 3.27 (2H, t, J=7.1 Hz),6.73 (1H, dd, J=8.8, 2.4 Hz), 6.85 (1H, d, J=2.4 Hz), 7.09 (1H, d, J=8.8Hz), 7.09 (1H, d, J=6.8 Hz), 7.19 (1H, dd, J=8.8, 6.8 Hz), 7.35 (1H, d,J=8.8 Hz), 8.66 (1H, br s). EIMS m/z (relative intensity): 467 (M⁺,100). Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N,8.99; S, 6.86. Found: C, 69.46; H, 8.07; N, 8.90; S, 6.96.

Example 45 Production of6-(6-methylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 2-amino-6-methylphenol (636 mg, 4.57 mmol) in ethanol(10 ml) was added potassium o-ethyl dithiocarbonate (801 mg, 5 mmol), atreflux under heating for 2 hours. The solvents were distilled off underreduced pressure; subsequently, the resulting residue was adjusted toacidity by using 1 N hydrochloric acid, and extracted with ethylacetate. The organic layer was washed with saturated sodium chloridesolution and dried over anhydrous sodium sulfate, from which thesolvents were distilled off. The resulting crude powder was crystallizedfrom acetone-hexane, to recover 2-mercapto-6-methylbenzoxazole (538 mgat a yield of 65%) as a yellowish brown crystal. To a solution of theoxazole (453 mg, 2.5 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (885 mg, 2.5 mmol) in DMF (8ml) were added potassium carbonate (387 mg, 2.8 mmol) and 18-crown-6 (66mg, 0.25 mmol), and the resulting mixture was stirred at 80° C. for 3hours. After the reaction solution was diluted with water, the organiclayer was extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (50 g of silica gel; elution solvents:hexane:acetone=5:1to 10:3); the resulting crystal was recrystallized fromacetone-ether-hexane, to recover the objective compound (908 mg at ayield of 82%) as a colorless needle-like crystal.

Melting Point: 112-114° C. IR (KBr) cm⁻¹: 3427, 3230, 2964, 1644, 1502.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.46-1.92 (6H, m), 2.36(2H,m), 2.41 (3H, S), 3.05 (2H, sept, J=6.8 Hz), 3.32 (2H, t, J=7.1 Hz),7.08 (1H, d, J=8.8 Hz), 7.09 (1H, d, J=6.6 Hz), 7.12 (1H, dd, J=8.1, 2.4Hz), 7.20 (1H, dd, J=8.8, 6.6 Hz), 7.36 (1H, dd, J=2.4, 0.7 Hz), 7.43(1H, d, J=8.1 Hz), 8.68 (1H, br s). EIMS m/z (relative intensity): 438(M⁺, 100). Elementary Analysis: C₂₆H₃₄N₂O₂S Required: C, 71.20; H, 7.81;N, 6.39; S, 7.31. Found: C, 71.08; H, 7.99; N, 6.27; S, 7.04.

Example 46 Production of6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 3-aminosalicylic acid (1.53 g, 10 mmol) in ethanol (70ml) was added potassium o-ethyl dithiocarbonate (3.2 g, 20 mmol), atreflux under heating for 2.5 hours. After the reaction solution was leftto stand for cooling, the solvents were distilled off under reducedpressure; the resulting residue was adjusted to acidity by using 1 Nhydrochloric acid; the resulting deposited precipitate was filtered anddried, to recover 7-carboxyl-2-mercaptobenzoxazole (1.3 g at a yield of67%) as a brown powder. To a solution of the carboxylic acid (976 mg,5.0 mmol) in methanol (50 ml) was added p-toluenesulfonic acidmonohydrate (95 mg, 0.5 mmol), for reflux under heating for 4 days.After the solution was left to stand for cooling, the solvents weredistilled off under reduced pressure; the resulting residue wasextracted with ethyl acetate. The organic layer was washed sequentiallywith water and saturated sodium chloride solution and dried overanhydrous sodium sulfate, from which the solvents were distilled off.The resulting solid material was crystallized from acetone-hexane, torecover 7-methoxycarbonyl-2-mercaptobenzoxazole (0.955 g at a yield of91%) as a brown powder. To a solution of the oxazole (837 mg, 4.0 mmol)and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (1.42 g, 4.0 mmol) inDMF (20 ml) were added potassium carbonate (608 mg, 4.4 mmol) and18-crown-6 (106 mg, 0.4 mmol), and the resulting mixture was stirred at80° C. for 2 hours. After the reaction solution was diluted with water,the organic layer was extracted with ethyl acetate. The organic layerwas washed sequentially with water and saturated sodium chloridesolution, and was dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (50 g of silica gel; elutionsolvents:hexane:acetone=5:1); the resulting crystal was recrystallizedfrom acetone-ether-hexane, to recover the objective compound (1.93 g ata yield of 100%) as a colorless needle-like crystal.

Melting Point: 118-119° C. IR (KBr) cm⁻¹: 3420, 2963, 1719, 1645, 1507.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.56 (2H, quint, J=7.3 Hz),1.73 (2H, quint, J=7.3 Hz), 1.90 (2H, quint, J=7.3 Hz), 2.37 (2H, t,J=7.3 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.3 Hz), 3.93 (3H,s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.42 (1H, t, J=7.9Hz), 7.80 (1H, dd, J=7.5, 0.9 Hz), 7.81 (1H, dd, J=7.9, 0.9 Hz), 8.68(1H, br s). EIMS m/z (relative intensity): 482 (M⁺), 176 (100).Elementary Analysis: C₂₇H₃₄N₂O₄S Required: C, 67.19; H, 7.10; N, 5.80;S, 6.64. Found: C, 67.42; H, 7.21; N, 5.84; S, 6.49.

Example 47 Production of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 26 except for the use of6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed to recover the objective compound as acolorless crystal.

Melting Point: 175-177° C. IR (KBr) cm⁻¹: 3241, 2963, 1691, 1647, 1507.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.57 (2H, quint, J=7.3 Hz),1.73 (2H, quint, J=7.3 Hz), 1.89 (2H, quint, J=7.3 Hz), 2.37 (2H, t,J=7.3 Hz), 3.08 (2H, sept, J=6.9 Hz), 3.38 (2H, t, J=7.3 Hz), 7.09 (2H,d, J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.37 (1H, t, J=7.9 Hz), 7.76 (2H,d, J=7.9 Hz), 8.70 (1H, br s). Elementary Analysis: C₂₆H₃₂N₂O₄SRequired: C, 66.64; H, 6.88; N, 5.98; S, 6.84. Found: C, 66.48; H, 6.87;N, 6.06; S, 6.60.

Example 48 Production of6-[7-hydroxymethylbenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 26 except for the use of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-carboxylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

Melting Point: 91-92° C. IR (KBr) cm⁻¹: 3394, 2966, 1647, 1485, 1428.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.56 (2H, quint, J=7.3 Hz),1.72 (2H, quint, J=7.3 Hz), 1.87 (2H, quint, J=7.3 Hz), 2.36 (2H, t,J=7.3 Hz), 3.08 (2H, sept, J=6.9 Hz), 3.36 (2H, t, J=7.3 Hz), 4.75 (2H,s), 4.88 (1H, br s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz),7.26 (1H, t, J=7.3 Hz), 7.29 (1H, dd, J=7.3, 1.7 Hz), 7.46 (1H, dd,J=7.3, 1.7 Hz), 8.69 (1H, br s). Elementary Analysis: C₂₆H₃₄N₂O₃SRequired: C, 68.69; H, 7.54; N, 6.16; S, 7.05. Found: C, 68.54; H, 7.68;N, 6.26; S, 6.95.

Example 49 Production of6-[7-(N,N-dimethylaminomethyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 27 except for the use of6-(7-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamideinstead of6-(4-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide,reaction progressed to recover the objective compound as a colorlesscrystal.

Melting Point: 102-104° C. IR (KBr) cm⁻¹: 3426, 3234, 1646, 1530, 1501.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.56 (2H, quint, J=7.3 Hz),1.72 (2H, quint, J=7.3 Hz), 1.87 (2H, quint, J=7.3 Hz), 2.24 (6H, s),2.36 (2H, t, J=7.3 Hz), 3.08 (2H, sept, J=6.9 Hz), 3.35 (2H, t, J=7.3Hz), 3.71 (2H, s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.23(1H, dd, J=7.6, 1.3 Hz), 7.27 (1H, t, J=7.6 Hz), 7.48 (1H, dd, J=7.6,1.3 Hz), 8.69 (1H, br s); Elementary Analysis: C₂₈H₃₉N₃O₂S Required: C,69.82; H, 8.16; N, 8.72; S, 6.65. Found: C, 69.88; H, 8.26; N, 8.65; S,6.66.

Example 50 Production of6-(7-N,N-dimethylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(328 mg, 0.7 mmol) in t-BuOH (6 ml) were sequentially addedtriethylamine (101 mg, 1.0 mmol) and diphenylphosphoryl azide (248 mg,0.9 mmol), at reflux under heating for 1.5 hours. After the resultingsolution was left to stand for cooling, water was added to the solution,which was then adjusted to alkalinity with an aqueous potassiumhydroxide solution, and extracted with ethyl acetate. The organic layerwas washed sequentially with water and saturated sodium chloridesolution, and was dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The resulting residue was purified bysilica gel column chromatography (10 g of silica gel; elution solvents;hexane:acetone=5:1), to recover6-(7-t-butoxycarbonylaminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(171 mg at a yield of 45%) as a colorless needle-like crystal.

The N-t-butoxycarbonylamino material (150 mg, 0.28 mmol) was dissolvedin trifluoroacetic acid (2 ml), with stirring at ambient temperature for2 hours. After distillation of trifluoroacetic acid, an aqueous sodiumhydrogen carbonate solution was added to the resulting residue, andextracted with ethyl acetate. The organic layer was washed sequentiallywith water and saturated sodium chloride solution, and was dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The resulting residue was purified by preparative thin layerchromatography (elution solvents; hexane:acetone=5:3), to recover6-(7-aminobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (126mg at a yield of 45%) as a pale brown needle-like crystal. To a solutionof the aniline (180 mg, 0.41 mmol) in acetonitrile (3 ml) was added anaqueous 37% formaldehyde solution (123 mg, 4.1 mmol) under cooling inice bath and was additionally added gradually sodium cyanoborohydride(100 mg, 1.6 mmol), followed by addition of acetic acid (0.05 ml). Tenminutes later, acetic acid (0.05 ml) was additionally added, withstirring for 20 minutes. To the reaction solution was added water, andextracted with ethyl acetate. The organic layer was sequentially washedwith an aqueous sodium hydrogen carbonate solution and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (12 g of silica gel; elutionsolvents:hexane:acetone=5:2), and the resulting crude crystal wasrecrystallized from acetone-hexane, to recover the objective compound(100 mg at a yield of 52%) as a colorless needle-like crystal.

Melting Point: 129-130° C. IR (KBr) cm⁻¹: 3435, 2965, 1645, 1537, 1497.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.56 (2H, quint, J=7.3 Hz),1.71 (2H, quint, J=7.3 Hz), 1.87 (2H, quint, J=7.3 Hz), 2.36 (2H, t,J=7.3 Hz), 3.02 (6H, s), 3.08 (2H, sept, J=6.9 Hz), 3.33 (2H, t, J=7.3Hz), 6.59 (1H, dd, J=8.0, 1.0 Hz), 6.95 (1H, dd, J=8.0, 1.0 Hz), 7.09(2H, d, J=7.6 Hz), 7.12 (1H, t, J=8.0 Hz), 7.19 (1H, t, J=7.6 Hz), 8.69(1H, br s). EIMS m/z (relative intensity): 467 (M⁺), 193 (100).Elementary Analysis: C₂₇H₃₇N₃O₂S Required: C, 69.34; H, 7.97; N, 8.99;S, 6.86. Found: C, 69.37; H, 8.06; N, 8.87; S, 6.85.

Example 51 Production of6-[7-(1-morpholino)methylbenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

To a solution of6-(7-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(182 mg, 0.4 mmol) in dichloromethane (4 ml) were added triethylamine(61 m g , 0.6 mmol) and 4-dimethylaminopyridine (5 mg, 0.04 mmol),followed by dropwise addition of methane sulfonylchloride (57 mg, 0.5mmol) under cooling in ice bath with stirring; the temperature wasallowed to warm temperature; and then, the resulting solution wasstirred for 15 minutes. The reaction solution was extracted with ethylacetate; the organic layer was washed sequentially with 0.5 Nhydrochloric acid and saturated sodium chloride solution, and was driedover anhydrous magnesium sulfate, from which the solvents were distilledoff. Morpholine (139 mg, 1.6 mmol) was added to a solution of theresulting residue in THF (4 ml), at reflux under heating for one hour.The reaction solution was extracted with ethyl acetate; the organiclayer was sequentially washed with an aqueous sodium hydrogen carbonatesolution and saturated sodium chloride solution and dried over anhydroussodium sulfate, from which the solvents were distilled off. Theresulting crude crystal was recrystallized from acetone-ether-hexane, torecover the objective compound (170 mg at a yield of 81%) as a colorlessneedle-like crystal.

Melting Point: 117-118° C. IR (KBr) cm⁻¹: 3440, 2963, 1647, 1501, 1428.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.56 (2H, quint, J=7.3 Hz),1.72 (2H, quint, J=7.3 Hz), 1.87 (2H, quint, J=7.3 Hz), 2.36 (2H, t,J=7.3 Hz), 2.42-2.45 (4H, m), 3.08 (2H, sept, J=6.9 Hz), 3.35 (2H, t,J=7.3 Hz), 3.56-3.59 (4H, m), 3.74 (2H, s), 7.09 (2H, d, J=7.6 Hz), 7.19(1H, t, J=7.6 Hz), 7.24 (1H, dd, J=7.6, 1.9 Hz), 7.27 (1H, t, J=7.6 Hz),7.48 (1H, dd, J=7.6, 1.9 Hz), 8.70 (1H, br s). Elementary Analysis:C₃₀H₄₁N₃O₃S Required: C, 68.80; H, 7.89; N, 8.02; S, 6.12. Found: C,68.72; H, 7.91; N, 7.92; S, 6.23.

Example 52 Production of6-[7-(tetrazol-5-yl)benzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(469 mg, 1.0 mmol) and 1-hydroxybenzotriazole ammonium salt (167 mg, 1.1mmol) in DMF (8 ml) was added WSC (211 mg, 1.1 mmol), and the resultingmixture was stirred at ambient temperature for 15 hours. After thereaction solution was extracted with ethyl acetate, the organic layerwas washed sequentially with diluted hydrochloric acid, water andsaturated sodium chloride solution, and was dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (30 g of silica gel;elution solvents:chloroform:methanol=5:2), to recover6-(7-carbamoylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(493 mg at a yield of 100%). The amide material (493 mg, 1.0 mmol) wasdissolved in phosphorus oxychloride (3 ml), with stirring at ambienttemperature for 24 hours. The reaction solution was poured into icewater, to decompose excess phosphorus oxychloride; the resultingsolution was neutralized with an aqueous potassium hydroxide solution,and extracted with ethyl acetate. The organic layer was washedsequentially with water and saturated sodium chloride solution, and wasdried over anhydrous sodium sulfate, from which the solvents weredistilled off. The resulting crude crystal was recrystallized fromacetone-ether-hexane, to recover6-(7-cyanobenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (315mg at a yield of 70%). To a solution of the nitrile material (300 mg,0.67 mmol) in DMF (3 ml) were added sodium azide (173.5 mg, 2.67 mmol)and ammonium chloride (142.8 mg, 2.67 mmol), with stirring at 120° C.for 15 hours. To the resulting reaction solution was added 1 Nhydrochloric acid, and resulting mixture was extracted with ethylacetate. The organic layer was washed with water and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The resulting residue was purified bysilica gel column chromatography (20 g of silica gel; elutionsolvents:chloroform:acetone:acetic acid=60:4:1). The resulting crystalwas recrystallized from acetone-ether-hexane, to recover the objectivecompound (115 mg at a yield of 35%) as a colorless crystal.

Melting Point: 218-220° C. IR (KBr) cm⁻¹: 3425, 2963, 1647, 1501, 1444.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.58 (2H, quint, J=7.3 Hz),1.73 (2H, quint, J=7.3 Hz), 1.92 (2H, quint, J=7.3 Hz), 2.37 (2H, t,J=7.3 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.42 (2H, t, J=7.3 Hz), 7.09 (2H,d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.50 (1H, t, J=7.8 Hz), 7.78 (1H,dd, J=7.8, 1.0 Hz), 7.89 (1H, dd, J=7.8, 1.0 Hz), 8.70 (1H, br s).Elementary Analysis: C₂₆H₃₂N₆O₂S Required: C, 63.39; H, 6.55; N, 17.06;S, 6.51. Found: C, 63.60; H, 6.63; N, 16.85; S, 6.45.

Example 53 Production of2-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)acetamide

In the same manner as in Example 46 except for the use of2-bromo-N-(2,6-diisopropylphenyl)acetamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless crystal.

Melting Point: 186-187° C. IR (KBr) cm⁻¹: 3437, 2965, 1733, 1637, 1367.1H-NMR (d₆-DMSO) δ: 1.17 (6H, d, J=6.8 Hz), 1.25 (6H, d, J=6.8 Hz), 2.90(2H, sept, J=6.8 Hz), 3.92 (3H, s), 4.27 (2H, s), 6.89 (1H, t, J=7.8Hz), 6.95 (1H, dd, J=7.8, 1.8 Hz), 7.28 (2H, d, J=7.8 Hz), 7.42 (1H, t,J=7.8 Hz), 7.56 (1H, dd, J=7.8, 1.7 Hz), 10.29 (1H, s). ElementaryAnalysis: C₂₃H₂₆N₂O₄S Required: C, 64.77; H, 6.14; N, 6.57; S, 7.52.Found: C, 64.92; H, 6.19; N, 6.65; S, 7.55.

Example 54 Production of9-(6-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

In the same manner as in Example 46 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

Melting Point: 122-124° C. IR (KBr) cm⁻¹: 3428, 3242, 2968, 1724, 1649.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.34-1.68 (10H, m), 1.85(2H, quint, J=7.1 Hz), 2.32 (2H, m), 3.09 (2H, sept, J=6.8 Hz), 3.36(2H, t, J=7.2 Hz), 3.93 (3H, s), 7.08 (1H, d, J=8.3 Hz), 7.09 (1H, d,J=6.6 Hz), 7.19 (1H, dd, J=8.3, 6.6 Hz), 7.40 (1H, t, J=7.8 Hz), 7.79(1H, dd, J=7.8, 1.2 Hz), 7.81 (1H, dd, J=7.8, 1.2 Hz), 8.62 (1H, br s).Elementary Analysis: C₃₀H₄₀N₂O₄S Required: C, 68.67; H, 7.68; N, 5.34;S, 6.11. Found: C, 68.78; H, 7.66; N, 5.41; S, 6.07.

Example 55 Production ofN-(2,6-diisopropylphenyl)-N′-[7-(7-methoxycarbonylbenzoxazol-2-ylthio)heptyl]urea

To a solution of 7-methoxycarbonyl-2-mercaptobenzoxazole (100 mg, 0.48mmol) and N-(2,6-diisopropylphenyl)-N′-(7-bromoheptyl)urea (190 mg,0.48mmol) in DMF (5 ml) were added potassium carbonate (73 mg, 0.53mmol) and 18-crown-6 (13 mg, 0.05 mmol), with stirring at 80° C. for 4hours. The reaction solution was diluted with water, and extracted withethyl acetate. The organic layer was sequentially washed with water andsaturated sodium chloride and dried over anhydrous magnesium sulfate,from which the solvents were distilled off. The resulting crystal wasrecrystallized from chloroform-ethyl acetate-hexane, to recover theobjective compound (184 mg at a yield of 73%) as a colorless crystal.

Melting Point: 179-181° C. IR (KBr) cm⁻¹: 3319, 2931, 1722, 1625, 1509.1H-NMR (d₆-DMSO) δ: 1.05 (12H, d, J=6.8 Hz), 1.25-1.42 (8H, m), 1.76(2H, quint, J=7.3 Hz), 3.00 (2H, dt, J=6.6, 6.1 Hz), 3.11 (2H, sept,J=6.8 Hz), 3.29 (2H, t, J=7.3 Hz), 3.86 (3H, s), 5.48 (1H, br s), 6.93(1H, br s), 7.00 (2H, d, J=7.6 Hz), 7.09 (1H, t, 7.6 Hz), 7.35 (1H, t,J=7.8 Hz), 7.75 (1H, dd, J=7.8, 1.2 Hz), 7.76 (1H, dd, J=7.6, 1.2 Hz).Elementary Analysis: C₂₉H₃₉N₃O₄S Required: C, 66.26; H, 7.48; N, 7.99;S, 6.10. Found: C, 65.99; H, 7.51; N, 8.20; S, 5.94.

Example 56 Production ofN-(2,6-diisopropylphenyl)-N′-[7-(7-methoxycarbonylbenzoxazol-2-ylsulfinyl)heptyl]urea

To a solution in dichloromethane-methanol (2:1, 9 ml) of theN-(2,6-diisopropylphenyl)-N′-[7-(7-methoxycarbonylbenzoxazol-2-ylthio)heptyl]urea(100 mg, 0.19 mmol) recovered in Example 55 was added m-chloroperbenzoicacid (60 mg, 0.19 mmol) at 0° C., with stirring at ambient temperaturefor 14 hours. The reaction solution was diluted with an aqueous sodiumhydrogen carbonate solution, and extracted with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The resultingresidue was purified by preparative thin layer chromatography (elutionsolvents; chloroform:acetone:methanol=75:25:1); the resulting crystalwas recrystallized from chloroform-ethyl acetate-hexane, to recover theobjective compound (66 mg at a yield of 64%) as a colorless crystal.

Melting Point: 145-147° C. IR (KBr) cm⁻¹: 3319, 2931, 1727, 1626, 1295.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.28-1.38 (4H, m),1.38-1.51 (4H, m), 1.70-1.90 (2H, m), 3.06 (2H, dd, J=6.6, 6.1 Hz), 3.19(2H, sept, J=6.8 Hz), 3.38-3.52 (2H, m), 3.98 (3H, s), 5.57 (1H, br s),7.01 (1H, br s), 7.09 (2H, d, J=7.3 Hz), 7.18 (1H, t, J=7.3 Hz), 7.62(1H, t, J=7.9 Hz), 8.06 (1H, dd, J=7.9, 1.2 Hz), 8.14 (1H, dd, J=7.9,1.2 Hz). Elementary Analysis: C₂₉H₃₉N₃O₅S Required: C, 64.30; H, 7.26;N, 7.76; S, 5.92. Found: C, 64.08; H, 7.53; N, 7.64; S, 5.94.

Example 57 Production ofN-(2,6-diisopropylphenyl)-N′-[7-(5-N,N-dimethylaminobenzoxazol-2-ylthio)heptyl]urea

To a solution of 2-mercapto-5-nitrobenzoxazole (200 mg, 1.02 mmol) andN-(7-bromoheptyl)-N′-(2,6-diisopropylphenyl)urea (484 mg, 1.02 mmol) inDMF (5 ml) were added potassium carbonate (185 mg, 1.34 mmol) and18-crown-6 (32 mg, 0.10 mmol),with stirring at 80° C. for 4 hours. Thereaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The resultingcrystal was recrystallized from chloroform-ethyl acetate-hexane, torecoverN-(2,6-diisopropylphenyl)-N′-[7-(5-nitrobenzoxazol-2-ylthio)heptyl]urea(500 mg at a yield of 96%) as a pale yellow crystal (at a melting pointof 134-135° C.).

The nitro material (387 mg, 0.76 mmol) was dissolved in acetic acid (8ml), followed by addition of zinc (987 mg, 15.1 mmol) under cooling inice bath, and the resulting mixture was stirred at ambient temperaturefor 15 minutes. After the reaction solution was diluted with ethylacetate and filtered through celite, the filtrate was adjusted toneutrality by using an aqueous sodium hydrogen carbonate solution. Theorganic layer was washed sequentially with an aqueous sodium hydrogencarbonate solution, water and saturated sodium chloride solution, andwas dried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (hexane:acetone=2:1); the resulting crystal wasrecrystallized from chloroform-ethyl acetate-ether, to recoverN-(2,6-diisopropylphenyl)-N′-[7-(5-aminobenzoxazol-2-ylthio)heptyl]urea(320 mg at a yield of 88%) as a pale yellow powdery crystal. To asolution of the amine (160 mg, 0.33 mmol) in acetonitrile (3 ml) weresequentially added a solution of an aqueous 37% formaldehyde solution(269 mg, 3.32 mmol) in acetonitrile (1 ml) and a suspension of sodiumcyanoborohydride (83 mg, 1.33 mmol) in acetonitrile (1 ml), followed bydropwise addition of acetic acid (27 μl) with stirring at ambienttemperature; and then, the resulting mixture was further stirred for 30minutes. After distillation of the solvents, the resulting residue wasdiluted with water, and extracted with ethyl acetate. The organic layerwas sequentially washed with water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate, from which thesolvents were distilled off. The residue was purified by preparativethin layer chromatography (elution solvents:hexane:acetone=2:1), and theresulting crystal was recrystallized from acetone-hexane, to recover theobjective compound (67 mg at a yield of 40%) as a colorless crystal.

Melting Point: 139-140° C. IR (KBr) cm⁻¹: 3321, 2929, 1629, 1571, 1149.1H-NMR (d₆-DMSO) δ: 1.06 (12H, d, J=6.8 Hz), 1.21-1.31 (4H, m),1.33-1.43 (4H, m), 1.71 (2H, quint, J=7.3 Hz), 2.83 (6H, s), 3.00 (2H,dt, J=6.6, 6.1 Hz), 3.11 (2H, sept, J=6.8 Hz), 3.21 (2H, t, J=7.3Hz),5.49 (1H, br s), 6.65 (1H, dd, J=9.0, 2.7 Hz), 6.81 (1H, d, J=2.7 Hz),6.93 (1H, br s), 7.00 (2H, d, J=8.1 Hz), 7.10 (1H, dd, J=8.1, 6.8 Hz),7.27 (1H, d, J=9.0 Hz). Elementary Analysis: C₂₉H₄₂N₄O₂S Required: C,68.20; H, 8.29; N, 10.97; S, 6.28. Found: C, 68.19; H, 8.27; N, 10.73;S, 6.13.

Example 58 Production of6-(7-methoxycarbonylbenzoxazol-2-ylthiosulfonyl)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(37 mg, 0.08 mmol) in methylene chloride (3 ml) was addedm-chloroperbenzoic acid (48 mg, 0.15 mmol) at −20° C., with stirring atambient temperature for 19 hours. The reaction solution was diluted withan aqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The resulting residue was purified by preparative thin layerchromatography (elution solvents; chloroform:acetone=4:1); and theresulting crystal was recrystallized from ethyl acetate-hexane, torecover the objective compound (15 mg at a yield of 38%) as a colorlessneedle-like crystal.

Melting Point: 145-147° C. IR (KBr) cm⁻¹: 3235, 2961, 1732, 1652, 1345,1159. 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=7.0 Hz), 1.54-1.63 (2H, m),1.66-1.75 (2H, m), 1.90-1.99 (2H, m), 2.31-2.39 (2H, m), 3.08 (2H, sept,J=7.0 Hz), 3.76 (2H, t, J=7.6 Hz), 3.99 (3H, s), 7.11 (2H, d, J=7.7 Hz),7.21 (1H, t, J=7.7 Hz), 7.70 (1H, t, J=8.1 Hz), 8.17 (1H, dd, J=7.6, 1.2Hz), 8.23 (1H, dd, J=8.1, 1.2 Hz), 8.72 (1H, br s). Elementary Analysis:C₂₇H₃₄N₂O₆S.1/6H₂O Required: C, 62.65; H, 6.69; N, 5.41; S, 5.92. Found:C, 62.68; H, 6.67; N, 5.47; S, 5.94.

Example 59 Production of6-[7-(2-N,N-dimethylaminoethyloxycarbonyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

A solution of 2,4,6-trichlorobenzoyl chloride (104 mg, 0.425 mmol) inTHF (2 ml) was dropwise added to a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(199 mg, 0.425 mmol) and tritylamine (52 mg, 0.510 mmol) in THF (1 ml)under cooling in ice bath. After stirring at ambient temperature for 35minutes, the deposited triethylamine hydrochloride salt was filteredoff. From the filtrate was distilled off the solvents under reducedpressure, and a solution of the resulting residue in chloroform (2 ml)was dropwise added to a solution of N,N-dimethyl ethanolamine (38 mg,0.425 mmol), and dimethylaminopyridine (5 mg, 0.043 mmol) in chloroform(1 ml) under cooling in ice bath, with stirring at ambient temperaturefor 40 minutes. After distillation of the solvents from the resultingreaction solution under reduced pressure, the resulting residue wasdiluted with ethyl acetate and water. The organic layer was washedsequentially with saturated sodium hydrogen carbonate solution, waterand saturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The resultingresidue was purified by silica gel column chromatography (20 g of silicagel; elutionsolvents:hexane:acetone=5:2/chloroform:methanol=100:1-20:1-10:1); andthe resulting crystal was recrystallized from acetone-hexane, to recoverthe objective compound (114 mg at a yield of 50%) as a colorlessneedle-like crystal.

Melting Point: 119-120° C. IR (KBr) cm⁻¹: 3423, 3232, 2966, 1721, 1647.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.53-1.96 (6H, m), 2.28(6H,s), 2.37 (2H,m), 2.71 (2H, t, J=5.9 Hz), 3.09 (2H, sept, J=6.8 Hz),3.39 (2H, t, J=7.2 Hz), 4.43 (2H, t, J=5.9 Hz), 7.08 (1H, d, J=8.5 Hz),7.09 (1H, d, J=6.7 Hz), 7.19 (1H, dd, J=8.5, 6.7 Hz), 7.40 (1H, t, J=7.8Hz), 7.80 (2H, dd, J=7.8, 1.5 Hz), 8.64 (1H, br s). Elementary Analysis:C₃₀H₄₁N₃O₄S Required: C, 66.76; H, 7.66; N, 7.79; S, 5.94. Found: C,66.75; H, 7.73; N, 7.80; S, 5.91.

Example 60 Production of6-[7-(2-N,N-dimethylaminoethyloxycarbamoyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

A solution of 2,4,6-trichlorobenzoyl chloride (104 mg, 0.425 mmol) inTHF (2 ml) was dropwise added to a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(199 mg, 0.425 mmol) and triethylamine (52 mg, 0.510 mmol) in THF (1 ml)under cooling in ice bath. After stirring at ambient temperature for 35minutes, the deposited triethylamine hydrochloride salt was filteredoff. From the filtrate was distilled off the solvents under reducedpressure, and a solution of the resulting residue in chloroform (2 ml)was dropwise added to a solution of N,N-dimethylethylenediamine (44 mg,0.5 mmol) and dimethylaminopyridine (6 mg, 0.005 mmol) in chloroform (1ml) under cooling in ice bath, with stirring at ambient temperature forone hour. After distillation of the solvents under reduced pressure fromthe resulting reaction solution, the resulting residue was diluted withethyl acetate and water. The organic layer was washed sequentially withsaturated sodium hydrogen carbonate solution, water and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off. The resulting residue was purified bysilica gel column chromatography (20 g of silica gel; elutionsolvents:chloroform:saturated ammonia-methanol=20:1); and the resultingcrystal was recrystallized from acetone-hexane, to recover the objectivecompound (60 mg at a yield of 22%) as a colorless crystal.

Melting Point: 135-137° C. IR (KBr) cm⁻¹: 3401, 3255, 2963, 1669, 1648.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.94 (6H, m), 2.26(6H, s), 2.37 (2H, m), 2.52 (2H, t, J=6.4 Hz), 3.09 (2H, sept, J=6.8Hz), 3.40 (2H, t, J=7.1 Hz), 3.46 (2H, q, J=6.4 Hz), 7.09 (1H, d, J=8.3Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H,dd, J=8.3, 6.6 Hz), 7.36 (1H, t,J=7.8 Hz), 7.67 (1H, dd, J=7.8, 1.2 Hz), 7.69 (1H, dd, J=7.8, 1.2 Hz),7.74 (1H, br s). 8.66 (1H, br s) Elementary Analysis: C₃₀H₄₂N₄O₃SRequired: C, 66.88; H, 7.86; N, 10.40; S, 6.84. Found: C, 66.71; H,7.82; N, 10.25; S, 6.67.

Example 61 Production of2-(7-methoxylcarbonylbenzoxazol-2-ylthio)-N-(2,4,6-trifluorophenyl)acetamide

In the same manner as in Example 46 except for the use of2-bromo-N-(2,4,6-trichlorophenyl)acetamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

Melting Point: 190-192° C. IR (KBr) cm⁻¹: 3426, 3252, 1723, 1679, 1508.1H-NMR (CDCl₃) δ: 3.99 (3H, s), 4.08 (2H, s), 6.70 (2H, m), 7.41 (1H, t,J=7.8 Hz), 7.81 (1H, dd, J=7.8, 1.0 Hz), 7.94 (1H, dd, J=7.8, 1.0 Hz),9.03 (1H, br s). Elementary Analysis: C₂₃H₂₆N₂O₄S Required: C, 51.52; H,2.80; N, 7.07; S, 14.38. Found: C, 51.44; H, 2.92; N, 7.03; S, 14.28.

Example 62 Production of6-(7-methoxylcarbonylbenzoxazol-2-ylthio)-N-(2,4,6-trimethoxyphenyl)hexanamide

To a solution of 2,4,6-trimethoxyaniline (180 mg, 0.98 mmol) andtriethylamine (111 mg, 1.1 mmol) in chloroform (4 ml) was dropwise added6-bromohexanoyl chloride (214 mg, 1.0 mmol) under cooling in ice bath,with stirring at ambient temperature for one hour. The reaction mixturewas concentrated, and the resulting residue was extracted with ethylacetate. The organic layer was washed with dilute hydrochloric acid, anaqueous sodium hydrogen carbonate solution, water, and saturated sodiumchloride solution and dried over anhydrous sodium sulfate, from whichthe solvents were distilled off; the resulting crystal wasrecrystallized from hexane-ether-chloroform, to recover the objectivecompound (320 mg at a yield of 89%) as a colorless needle-like crystal.In the same manner as in Example 46 except for the use of6-bromo-N-(2,4,6-trimethoxyphenyl)hexanamide instead of6-bromo-N-(2,6-diisopropylphenyl)hexanamide, subsequently, reactionprogressed to recover the objective compound as a colorless needle-likecrystal.

Melting Point: 136-138° C. IR (KBr) cm⁻¹: 3251, 2935, 1727, 1660, 1507.1H-NMR (d₆-DMSO) δ: 1.52 (2H, quint, J=7.3 Hz), 1.64 (2H, quint, J=7.3Hz), 1.85 (2H, quint, J=7.3 Hz), 2.19 (2H, t, J=7.3 Hz), 3.36 (2H, t,J=7.3 Hz), 3.71 (6H, s), 3.76 (3H, S), 3.93 (3H, s), 6.22 (2H, s), 7.42(1H, t, J=7.8 Hz), 7.80 (1H, dd, J=7.8, 1.2 Hz),7.84 (1H, dd, J=7.8, 1.2Hz), 7.92 (1H, br S). Elementary Analysis: C₂₄H₂₈N₂O₇S Required: C,59.00; H, 5.78; N, 5.73; S, 6.56. Found: c, 58.94; H, 5.82; N, 5.74; S,6.55

Example 63 Production of6-(5-methoxycarbonylbenzimidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 5-methoxycarbonyl-2-mercaptobenzimidazole (100 mg, 0.48mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (170 mg, 0.48mmol) in DMF (4 ml) were added potassium carbonate (73 mg, 0.53 mmol)and 18-crown-6 (13mg, 0.05 mmol),with stirring at 80° C. for 4 hours.The reaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The resultingcrystal was purified by preparative thin layer chromatography (elutionsolvents:chloroform:acetone saturated ammonia methanol=80:20:1); and theresulting crystal was recrystallized from ethyl acetate-hexane, torecover the objective compound (137 mg at a yield of 59%) as a colorlesscrystal.

Melting Point: 190-192° C. IR (KBr) cm⁻¹: 3178, 2962, 1716, 1655, 1434,1297. 1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.51-1.62 (2H, m),1.68-1.77 (2H, m), 1.77-1.87 (2H, m), 2.33-2.41 (2H, m), 3.10 (2H, sept,J=6.8 Hz), 3.35 (2H, t, J=7.2 Hz), 3.87 (3H, s), 7.10 (1H, d, J=8.1 Hz),7.11 (1H, d, J=7.3 Hz), 7.21 (1H, dd, J=8.1, 7.3 Hz), 7.47 (1H, d, J=8.3Hz), 7.77 (1H, dd, J=8.3, 1.6 Hz), 8.03 (1H, br s), 8.71 (1H, br s).Elementary Analysis: C₂₇H₃₅N₃O₃S.0.4H₂O Required: C, 66.34; H, 7.38; N,8.60; S, 6.56. Found: C, 66.25; H, 7.37; N, 8.42; S, 6.40.

Example 64 Production of6-(5-N,N-dimethylaminobenzimidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 2-mercapto-5-nitrobenzimidazole (195 mg, 1.0 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (354 mg, 1.0 mmol) in DMF (7ml) were added potassium carbonate (152 mg, 1.1 mmol) and 18-crown-6 (26mg, 0.1 mmol),with stirring at 80° C. for 3 hours. The reaction solutionwas diluted with water, and extracted with ethyl acetate. The organiclayer was sequentially washed with water and saturated sodium chloridesolution and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off, to recover6-(5-nitrobenzimidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(600 mg) as a pale yellow oil. The nitro material (640 mg, 1.37 mmol)was dissolved in acetic acid (10 ml), followed by addition of zinc (1.79g, 27.3 mmol) under cooling in ice bath, with stirring at ambienttemperature for 15 minutes. The reaction solution was filtered throughcelite; the resulting filtrate was adjusted to neutrality by using anaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate. The organic layer was washed sequentially with an aqueoussodium hydrogen carbonate solution, water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate solution, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (elution solvents; chloroform:methanol=10:1), torecover6-(5-aminobenzimidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(451 mg at a yield of 75%) as a pale yellow oil.

To a solution of the aniline (398 mg, 0.91 mmol) in acetonitrile (7 ml)were added sequentially an aqueous 37% formaldehyde solution (736 mg,9.07 mmol) and a suspension of sodium cyanoborohydride (228 mg, 3.63mmol) in acetonitrile (7 ml), followed by dropwise addition of aceticacid (73 μl) while the resulting mixture was stirred at ambienttemperature; and then, the resulting mixture was further stirred for 30minutes. After distillation of the solvents, the resulting residue wasdiluted with water, and extracted with ethyl acetate. The organic layerwas sequentially washed with water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate, from which thesolvents were distilled off. The residue was purified by preparativethin layer chromatography (elution solvents:chloroform:saturated ammoniamethanol=10:1), and the resulting crystal was recrystallized fromchloroform-ethyl acetate-hexane, to recover the objective compound (53mg at a yield of 13%) as a pale brown powdery crystal.

Melting Point: 109-111° C. IR (KBr) cm⁻¹: 3235, 2962, 1651, 1519, 1440.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.51-1.59 (2H, m),1.66-1.82 (4H, m), 2.32-2.40 (2H, m), 2.89 (6H, s), 3.10 (2H, sept,J=6.8 Hz), 3.24 (2H, t, J=7.1 Hz), 6.68-6.76 (2H, m), 7.11 (2H, d, J=7.6Hz), 7.18-7.28 (2H, m), 8.71 (1H, br s). Elementary Analysis: C₂₇H₃₈N₄OSRequired: C, 69.49; H, 8.21; N, 12.01; S, 6.87. Found: C, 69.31; H,8.20; N, 11.90;. S, 6.91.

Example 65 Production of6-(6-N,N-dimethylaminobenzothiazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 2-mercapto-6-nitrobenzothiazole (212 mg, 1.0 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (354 mg, 1.0 mmol) in DMF (6ml) were added potassium carbonate (152 mg, 1.1 mmol) and 18-crown-6 (26mg, 0.1 mmol),with stirring at 80° C. for 2 hours. The reaction solutionwas diluted with water and ethyl acetate. The organic layer wassequentially washed with an aqueous sodium hydrogen carbonate solution,water, dilute hydrochloric acid and saturated sodium chloride solutionand dried over anhydrous magnesium sulfate, from which the solvents weredistilled off. The residue was purified by silica gel columnchromatography (50 g of silica gel; elutionsolvents:hexane:acetone=5:2), to recover6-(6-nitrobenzothiazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(490 mg at a yield of 100%) as a pale yellow oil. The nitro material(490 mg, 1.0 mmol) was dissolved in acetic acid (5 ml), followed byaddition of zinc (1.3 g, 20 mmol) under cooling in ice bath, withstirring at ambient temperature for 20 minutes. The reaction solutionwas diluted with ethyl acetate and filtered through celite; the filtratewas adjusted to neutrality by using an aqueous sodium hydrogen carbonatesolution. The organic layer was sequentially washed with an aqueoussodium hydrogen carbonate solution, water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate, from which thesolvents were distilled off, to recover6-(6-aminobenzothiazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(426 mg). To a solution of the amine material (380 mg, 0.83 mmol) inacetonitrile (4 ml) were added sequentially an aqueous 37% formaldehydesolution (325 mg, 4.0 mmol) and sodium cyanoborohydride (100.5 mg, 1.6mmol), followed by dropwise addition of acetic acid (0.1 ml) while theresulting mixture was stirred at ambient temperature; and then, theresulting mixture was further stirred for 2 hours as it was.Additionally, acetic acid (0.1 ml) was dropwise added to the mixture,which was stirred for 30 minutes. After distillation of the solventsunder reduced pressure, the resulting residue was diluted with ethylacetate and water. The organic layer was sequentially washed with anaqueous sodium hydrogen carbonate solution, water and saturated sodiumchloride solution and dried over anhydrous magnesium sulfate, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (elution solvents:hexane:acetone=10:1 to 5:1), andthe resulting crystal was recrystallized fromacetone-dichloromethane-hexane, to recover the objective compound (152mg at a yield of 38%) as a colorless needle-like crystal.

Melting Point: 146-147° C. IR (KBr) cm⁻¹: 3427, 3233, 1648, 1602, 1460.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.50-1.60 (6H, m),1.68-1.75 (2H, m), 1.78-1.85 (2H, m), 2.35 (2H, t, J=6.8 Hz), 2.94 (6H,s), 3.08 (2H, sept, J=6.8 Hz), 3.29 (2H, t, J=7.3 Hz), 6.90 (1H, dd,J=9.0, 2.6 Hz), 7.09 (1H, d, J=7.6 Hz), 7.17 (1H, d, J=2.6 Hz), 7.20(1H, t, J=7.6 Hz), 7.62 (1H, d, J=9.0 Hz), 8.70 (1H, br s). ElementaryAnalysis: C₂₇H₃₇N₃OS₂ Required: C, 67.04; H, 7.71; N, 8.69; S, 13.26.Found: C, 67.00; H, 7.83; N, 8.70; S, 13.19.

Example 66 Production of 6-[(±)-3a,7a-trans-3a,4,5,6,7,7a-hexahydrobenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

A mixture solution of (±)-trans-2-aminocyclohexanol (500 mg, 4.34 mmol),carbon disulfide (1 ml) and an aqueous 0.5 N sodium hydroxide solution(1 ml) was refluxed under heating for 4 hours. The reaction solution wasextracted with ether and then isolated; to the aqueous layer was addedacetic acid to adjust the layer to acidity, and the resulting mixturewas extracted with ether. The organic layer was washed with water anddried over anhydrous magnesium sulfate, from which the solvents weredistilled off.

To a solution of the resulting(±)-2-mercapto-3a,7a-trans-3a,4,5,6,7,7a-hexahydrobenzoxazole (67 mg,0.43 mmol) and 6-bromo-N-(2,6-diisopropylphenyl)hexanamide (151 mg, 0.43mmol) in DMF (3 ml) were added potassium carbonate (65 mg, 0.47 mmol)and 18-crown-6 (11 mg, 0.04 mmol), with stirring at 80° C. for 6 hours.The reaction solution was diluted with water, and extracted with ethylacetate. The organic layer was washed with water and dried overanhydrous magnesium sulfate, from which the solvents were distilled off.The residue was purified by preparative thin layer chromatography(elution solvents:hexane:acetone=3:1); and the resulting crystal wasrecrystallized from ethyl acetate-hexane, to recover the objectivecompound (53 mg at a yield of 29%) as a colorless needle-like crystal.

Melting Point: 121-123° C. IR (KBr) cm⁻¹: 3242, 2961, 1652, 1570, 1525.1H-NMR (d₆-DMSO) δ: 1.15 (12H, d, J=6.8 Hz), 1.28-1.87 (12H, m),2.15-2.27 (2H, m), 2.30-2.40 (2H, m), 2.95-3.05 (1H, m), 3.01 (2H, t,J=7.1 Hz), 3.11 (2H, sept, J=6.8 Hz), 3.66 (1H, dt, J=11.5 ,3.8 Hz),7.12 (1H, d, J=8.6 Hz), 7.12 (1H, d, J=6.8 Hz), 7.22 (1H, dd, J=8.6, 6.8Hz), 8.70 (1H, br s). EIMS m/z (relative intensity): 430 (M⁺), 204(100). Elementary Analysis: C₂₆H₃₈N₂O₂ S Required: C, 69.73; H, 8.89; N,6.50. Found: C, 69.56; H, 9.00; N, 6.30.

Example 67 Production of 6-[(±)3a,7a-cis-3a,4,5,6,7,7a-hexahydrobenzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 66 except for the use of(±)-cis-2-aminocyclohexanol instead of (±)-trans-2-aminocyclohexanol,reaction progressed to recover (±)-2-mercapto-3a,7a-cis-3a,4,5,6,7,7a-hexahydrobenzoxazole; subsequently, in the samemanner by using 6-bromo-N-(2,6-diisopropylphenyl)hexanamide, reactionprogressed, to recover the objective compound as a colorless needle-likecrystal.

Melting Point: 96-97° C. IR (KBr) cm⁻¹: 3253, 2964, 2939, 1647, 1592.1H-NMR (d₆-DMSO) δ: 1.15 (12H, d, J=6.8 Hz), 1.32-1.83 (14H, m), 2.36(2H, m), 3.02 (2H, t, J=7.3 Hz), 3.11 (2H, sept, J=6.8 Hz), 3.97 (1H,dt, J=8.1, 5.6 Hz), 4.65 (1H, d t, J=8.1, 5.3 Hz), 7.12 (1H, d, J=8.6Hz), 7.12 (1H, d, J=6.8 Hz), 7.23 (1H, dd, J=8.6, 6.8 Hz), 8.71 (1H, brs). EIMS m/z (relative intensity): 430 (M⁺), 204 (100). ElementaryAnalysis: C₂₅H₃₈N₂O₂S Required: C, 69.73; H, 8.89; N, 6.50; S, 7.44.Found: C, 69.51; H, 8.90; N, 6.35; S, 7.62

Example 68 Production of6-(imidazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 2-mercaptoimidazole (56 mg, 0.56 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (198 mg, 0.56 mmol) in DMF(4 ml) were added potassium carbonate (85 mg, 0.62 mmol) and 18-crown-6(15 mg, 0.06 mmol), with stirring at 80° C. for 6 hours. The reactionsolution was diluted with water, and extracted with ethyl acetate. Theorganic layer was washed with water and dried over anhydrous magnesiumsulfate, from which the solvents were distilled off. The residue waspurified by preparative thin layer chromatography (elutionsolvents:chloroform:methanol=20:1); and the resulting crystal wasrecrystallized from methanol-ethyl acetate-hexane, to recover theobjective compound (76 mg at a yield of 36%) as a colorless needle-likecrystal.

Melting Point: 190-191° C. IR (KBr) cm⁻¹: 3235, 2960, 1644, 1530, 1093.1H-NMR (d₆-DMSO) δ: 1.14 (12H, d, J=6.8 Hz), 1.45-1.60 (2H, m),1.63-1.77 (4H, m), 2.30-2.40 (3H, m), 3.05 (2H, t, J=7.3 Hz), 3.10 (2H,sept, J=6.8 Hz), 7.00-7.09 (2H, m), 7.12 (1H, d, J=7.1 Hz), 7.12 (1H, d,J=6.6 Hz), 7.22 (1H, dd, J=7.1, 6.6 Hz), 8.70 (1H, br s). EIMS m/z(relative intensity): 373 (M⁺, 100). Elementary Analysis: C₂₁H₃₁N₃OSRequired: C, 67.52; H, 8.36; N, 11.25; S, 8.58. Found: C, 67.39; H,8.34; N, 11.11; S, 8.35.

Example 69 Production of6-naphtho[2,3-d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 3-amino-2-naphthol (1.59 g, 10 mmol) in ethanol (50 ml)was added potassium o-ethyl dithiocarbonate (3.21 g, 20 mmol), at refluxunder heating for 24 hours. After the solvents were distilled off underreduced pressure, the resulting residue was diluted with water andadjusted to acidity by using conc. hydrochloric acid, and extracted withethyl acetate. The organic layer was washed with saturated sodiumchloride solution and dried over anhydrous sodium sulfate. After thesolvents were distilled off, the resulting residue was purified bysilica gel column chromatography (200 g of silica gel; elution solvents;hexane:acetone=5:1 to 5:2); the resulting crystal was recrystallizedfrom acetone-hexane, to recover 2-mercaptonaphtho[2,3-d]oxazole (1.28 gat a yield of 64%) as a pale brown crystal.

To a solution of the oxazole (102 mg, 0.5 mmol) and6-bromo-N-(2,6-diisopropylphenyl)hexanamide (177 mg, 0.5 mmol) in DMF (3ml) were added potassium carbonate (104 mg, 0.75 mmol) and 18-crown-6(13 mg, 0.05 mmol), with stirring at 80° C. for 2 hours. The reactionsolution was diluted with water and extracted with ether. The organiclayer was washed sequentially with water and saturated sodium chloridesolution and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (25 g of silica gel; elutionsolvents:hexane:acetone=5:1); the resulting crystal was recrystallizedfrom acetone-hexane, to recover the objective compound (161 mg at ayield of 68%) as a colorless crystal.

Melting Point: 159-160° C. IR (KBr) cm⁻¹: 3425, 3230, 2964, 1647, 1516.1H-NMR (d₆-DMSO) δ: 1.13 (12H, d, J=6.8 Hz), 1.54-1.97 (6H, m), 2.38(2H, m), 3.10 (2H, sept, J=6.8 Hz), 3.42 (2H, t, J=7.2 Hz), 7.09 (1H, d,J=8.8 Hz), 7.09 (1H, d, J=6.6 Hz), 7.19 (1H, dd, J=8.8, 6.6 Hz),7.41-7.50 (2H, m), 7.93-8.03 (4H, m), 8.67 (1H, br s), EIMS m/z(relative intensity): 474 (M⁺, 100). Elementary Analysis: C₂₉H₃₄N₂O₂SRequired: C, 73.38; H, 7.22; N, 5.90; S, 6.75. Found: C, 73.38; H, 7.26;N, 5.85; S, 6.65.

Example 70 Production of6-(5-dimethylphenylsilylmethyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of6-(5-hydroxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(118 mg, 0.27 mmol) in DMF (1 ml) were sequentially added 18-crown-6(7.1 mg, 0.027 mmol), potassium carbonate (56 mg, 0.40 mmol) andchloromethyldimethylphenylsilane (50 mg, 0.27 mmol), with stirring at80° C. for 4 hours. To the reaction solution was again addedchloromethyldimethylphenylsilane (25 mg, 0.13 mmol), with stirring at80° C. for 3 hours. Still additionally, chloromethyldimethylphenylsilane(25 mg, 0.13 mmol) was added, with stirring at 80° C. for 90 minutes.The reaction mixture was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (20 g of silica gel;elution solvents:hexane:acetone=5:1), to recover the objective compound(108 mg at a yield of 68%) as a colorless needle-like crystal.

Melting Point: 106-108° C. IR (KBr) cm⁻¹: 3433, 3222, 2962, 1648, 1472.1H-NMR (d₆-DMSO) δ: 0.38 (6H, s), 1.12 (12H, d, J=6.8 Hz) 1.50-1.91 (6H,m), 2.34-2.39 (2H, m), 3.09 (2H, sept., J=6.8 Hz), 3.32 (2H, t, J=7.1Hz), 3.91 (2H, s), 6.87 (1H, dd, J=8.8, 2.5 Hz), 7.08 (1H, d, J=8.3 Hz),7.09 (1H, d, J=6.8 Hz), 7.16 (1H, d, J=2.5 Hz), 7.19 (1H, dd, J=8.3, 6.8Hz), 7.32-7.39 (4H, m), 7.56-7.62 (2H, m), 8.65 (1H, br s) EIMS m/z(relative intensity): 558 (M⁺, 100). Elementary Analysis: C₃₄H₄₄N₂O₃SSiRequired: C, 69.35; H, 7.53; N, 4.76; S, 5.45. Found: C, 69.26; H, 7.55;N, 4.76; S, 5.44.

Example 71 Production ofN-(2,6-diisopropylphenyl)-N′-heptyl-N′-[6-(7-methoxycarbonylbenzoxazol-2-ylthio)hexyl]urea

6-Hexanolactone (2.28 g, 20 mmol) and heptylamine (2.42 g, 21 mmol) werestirred together at 100° C. for 2 hours. The reaction mixture wasdiluted with water, and extracted with ethyl acetate; the organic layerwas washed with 1 N hydrochloric acid, water, an aqueous saturatedsodium hydrogen carbonate solution and saturated sodium chloridesolution and dried over anhydrous sodium sulfate. After the solventswere distilled off, the resulting residue was purified by silica gelcolumn chromatography (150 g of silica gel; elutionsolvents:hexane:acetone=5:2 to 5:3), to recover6-hydroxy-N-heptylhexanamide (2.1 g at a yield of 46%) as a colorlessneedle-like crystal (m.p.: 56-58° C.).

To a solution of the amide (2.6 g, 11 mmol) in THF (40 ml) with stirringunder cooling in ice bath was added lithium aluminium hydride (1.1 g, 30mmol) under argon atomospher, with stirring at room temperature for onehour, at 80° C. for 2 hours and at 90° C. for one hour. The resultingmixture was diluted with ether (300 ml), followed by addition of severaldroplets of an aqueous ammonium chloride solution, with stirring at roomtemperature for 30 minutes. Insoluble matters were filtered off throughcelite; the filtrate was concentrated; and the residue was extractedwith diluted hydrochloric acid. The aqueous layer was washed with etherand ethyl acetate, and was then adjusted to alkalinity by usingpotassium carbonate, and extracted with chloroform extraction. Theorganic layer was washed with saturated sodium chloride solution anddried over potassium carbonate, from which the solvents were distilledoff. The resulting solid material was crystallized inacetone-ether-hexane, to recover 6-heptylamino-1-hexanol (1.42 g at ayield of 59%) as a colorless needle-like crystal (m.p.: 50 to 52° C.).

To a solution of the aminoalcohol (646 mg, 3.0 mmol) in chloroform (4ml) was dropwise added 2,6-diisopropylphenylisocyanate (610 mg, 3.0mmol) under cooling in ice bath water, with stirring at ambienttemperature for 2 hours. To the resulting reaction mixture was addedhexane, to deposit crystal, which was then filtered and recovered asN-(2,6-diisopropylphenyl)-N′-heptyl-N′-(6-hydroxyhexyl)urea (1.09 g at ayield of 87%) as a colorless needle-like crystal (m.p.: 137-139° C.).

To a solution of the urea (419 mg, 1.0 mmol) and 4-dimethylaminopyridine(12 mg, 0.1 mmol) in THF (5 ml) were added triethylamine (142 mg, 1.4mmol) and methanesulfonyl chloride (137 mg, 1.2 mmol) under cooling inice bath, and the resulting mixture was stirred at the temperature for 2hours. After insoluble matters were filtered off, the resulting solutionwas concentrated. The residue was extracted with ethyl acetate; theorganic layer was washed with water and saturated sodium chloridesolution and dried over sodium sulfate, from which the solvents weredistilled off. The resulting solid matter was crystallized inhexane-ethyl acetate, to recover6-[3-(2,6-diisopropylphenyl)-1-heptylureido]hexyl methanesulfonate (433mg at a yield of 87%) as a colorless needle-like crystal (m.p.: 140-141°C.).

A solution of the methanesulfonate (199 mg, 0.4 mmol) in DMF (2 ml) wasadded to a solution of 7-methoxycarbonyl-2-mercaptobenzoxazole (84 mg,0.4 mmol), potassium carbonate (83 mg, 0.6 mmol) and 18-crown-6 (11 mg,0.04 mmol) in DMF (1 ml), with stirring at 80° C. for 90 minutes. Thereaction solution was diluted with water, and extracted with ethylacetate. The organic layer was washed sequentially with water andsaturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (25 g of silica gel;elution solvents:hexane:acetone=20:1 to 5:1), to recover the objectivecompound (131 mg at a yield of 54%) as a colorless needle-like crystal.

Melting Point: 120-121° C. IR (KBr) cm⁻¹: 3425, 3328, 1728, 1624, 1507.1H-NMR (d₆-DMSO) δ: 0.86 (3H, t, J=6.8 Hz), 1.11 (12H, d, J=6.8 Hz)1.26-1.31 (8H, m), 1.37-1.42 (2H, m), 1.47-1.60 (6H, m), 1.81-1.88 (2H,m), 3.14 (2H, sept, J=6.8 Hz), 3.25-3.31 (2H, m), 3.36 (1H, t, J=7.1Hz), 3.93 (3H, s) 7.04 (1H, br s), 7.05 (2H, d, J=7.8 Hz), 7.15 (1H, t,J=7.8 Hz), 7.41 (1H, m), 7.78-7.84 (2H, m) EIMS m/z (relativeintensity): 609 (M⁺), 189 (100) Elementary Analysis: C₃₅H₅₁N₃O₄SRequired: C, 68.93; H, 8.43; N, 6.89; S, 5.26. Found: C, 69.09; H, 8.50;N, 6.84; S, 5.10.

Example 72 Production ofN-(2,6-diisopropylphenyl)-N′-heptyl-N′-[6-(oxazolo[4,5-b]pyridin-2-ylthio)hexyl]urea

In the same manner as in Example 71 except for the use of2-mercaptooxazolo[4,5-b]pyridine instead of7-methoxycarbonyl-2-mercaptobenzoxazole, reaction progressed to recoverthe objective compound as a colorless needle-like crystal.

Melting Point: 124-125° C. IR (KBr) cm⁻¹: 3420, 3328, 1624, 1507, 1402.1H-NMR (d₆-DMSO) δ: 0.86 (3H, t, J=7.0 Hz), 1.11 (2.4H, d, J=6.8 Hz),1.11 (9.6H, d, J=6.8 Hz), 1.26-1.32 (8H, m), 1.37-1.43 (2H, m),1.47-1.60 (6H, m), 1.81-1.93 (2H, m), 3.10-3.19 (2H, m), 3.25-3.31 (2H,m), 3.38 (1.6H, t, J=7.2 Hz), 4.22 (0.4H, t, J=7.2 Hz), 7.05 (1H, d,J=8.3 Hz), 7.06 (1H, br s), 7.06 (1H, d, J=6.8 Hz), 7.15 (1H, dd, J=8.3,6.8 Hz), 7.28 (0.8H, dd, J=8.3, 4.9 Hz), 7.30 (0.2H, dd, J=8.3, 4.9 Hz),7.84 (0.2H, dd, J=8.3, 1.5 Hz), 7.95 (0.8H, dd, J=8.3, 1.5 Hz), 8.28(0.2H, dd, J=4.9, 1.5 Hz), 8.39 (0.8H, dd, J=4.9, 1.5 Hz). EIMS m/z(relative intensity): 552 (M⁺), 188 (100) Elementary Analysis:C₃₂H₄₈N₄O₂S Required: C, 69.53; H, 8.75; N, 10.13; S, 5.80. Found: C,69.65; H, 8.83; N, 10.09; S, 5.86.

Example 73 Production of2-(7-trifluoromethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)acetamide

In the same manner as in Example 11 except for the use of2-nitro-6-trifluoromethylphenol instead of3-hydroxy-6-methyl-nitropyridine, reaction progressed to recover2-mercapto-7-trifluoromethylbenzoxazole (110 mg, 0.5 mmol); to asolution of the 2-mercapto-7-trifluoromethylbenzoxazole (110 mg, 0.5mmol) and 2-bromo-N-(2,6-diisopropylphenyl)acetamide (149 mg, 0.5 mmol)was added potassium carbonate (76 mg, 0.55 mmol), with stirring atambient temperature for one hour. The reaction solution was diluted withwater, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solutionand dried over sodium sulfate, from which the solvents were distilledoff. The residue was purified by preparative thin layer chromatography(elution solvents:hexane:acetone=5:2), to recover the objective compound(61 mg at a yield of 28%) as a colorless needle-like crystal.

Melting Point: 172-173° C. IR (KBr) cm⁻¹: 3432, 3267, 2967, 1664, 1509.1H-NMR (CDCl₃) δ: 1.04-1.12 (12H, m), 2.99 (2H, sept, J=6.9 Hz), 4.15(2H, s), 7.14 (2H, d, J=7.8 Hz), 7.28 (1H, t, J=7.8 Hz), 7.42 (1H, t,J=7.9 Hz), 7.55 (1H, d, J=7.9 Hz), 7.76 (1H, d, J=7.9 Hz), 8.36 (1H, brs). EIMS m/z (relative intensity): 436 (M⁺, 100) Elementary Analysis:C₂₂H₂₃F₃N₂O₂S Required: C, 60.54; H, 5.31; N, 6.42; F, 13.06. Found: C,60.42; H, 5.32; N, 6.39; F, 12.95.

Example 74 Production of6-(7-trifluoromethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 73 except for the use of6-bromo-N-(2,6-diisopropylphenyl)hexanamide instead of2-bromo-N-(2,6-diisopropylphenyl)acetamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

Melting Point: 130° C. IR (KBr) cm⁻¹: 3227, 2968, 1645, 1534, 1490.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=7.0 Hz), 1.56 (2H, m), 1.72 (2H, m),1.89 (2H, m), 2.36 (2H, m), 3.08 (2H, sept, 6.8 Hz), 3.39 (2H, t, J=7.1Hz), 7.09 (2H, d, J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.50 (1H, t, J=7.9Hz), 7.59 (1H, d, J=7.9 Hz), 7.88 (1H, d, J=7.9 Hz), 8.69 (1H, br s).EIMS m/z (relative intensity): 492 (M⁺), 69 (100). Elementary Analysis:C₂₆H₃₁F₃N₂O₂S Required: C, 63.40; H, 6.34; N, 5.69. Found: C, 63.11; H,6.43; N, 5.65.

Example 75 Production of9-(7-trifluoromethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide

In the same manner as in Example 73 except for the use of9-bromo-N-(2,6-diisopropylphenyl)nonanamide instead of2-bromo-N-(2,6-diisopropylphenyl)acetamide, reaction progressed torecover the objective compound as a colorless needle-like crystal.

Melting Point: 82-84° C. IR (KBr) cm⁻¹: 3436, 3244, 1648, 1506, 1332.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.34-1.41 (6H, m),1.44-1.51 (2H, m), 1.61-1.68 (2H, m), 1.84 (2H, quint, J=7.2 Hz).2.29-2.35 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.37 (2H, t, J=7.2 Hz),7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.50 (1H, ddd, J=8.1,7.8, 0.7 Hz), 7.59 (1H, d, J=7.8 Hz), 7.88 (1H, d, J=8.1 Hz), 8.67 (1H,br s). EIMS m/z (relative intensity): 534 (M⁺, 100) Elementary Analysis:C₂₉H₃₇F₃N₂O₂S Required: C, 65.15; H, 6.97; N, 5.24; F, 10.66. Found: C,65.31; H, 6.92; N, 5.29; F, 10.51.

Example 76 Production of6-(5-trifluoromethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl]hexanamide

In the same manner as in Example 11 except for the use of2-nitro-4-trifluoromethylphenol instead of3-hydroxy-6-methyl-2-nitropyridine, reaction progressed to recover2-mercapto-5-trifluoromethylbenzoxazole. The resulting product wassubjected to the same reaction in the same manner as in Example 74, torecover the objective compound as a colorless crystal.

Melting Point: 98° C. IR (KBr) cm⁻¹: 3232, 2964, 1648 1500. 1H-NMR(d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.56 (2H, m), 1.72 (2H, m), 1.88(2H, m), 2.36 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.40 (2H, t, J=7.0Hz), 7.10 (2H, d, J=7.3 Hz), 7.20 (1H, t, J=7.3 Hz), 7.63 (1H, d, J=8.6Hz), 7.79 (1H, d, J=8.6 Hz), 7.92 (1H, s), 8.70 (1H, br s). EIMS m/z(relative intensity): 492 (M⁺, 100). Elementary Analysis: C₂₆H₃₁F₃N₂O₂SRequired: C, 63.40; H, 6.34; N, 5.69. Found: C, 63.47; H, 6.62; N, 5.45.

Example 77 Production of6-(7-tert-butylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 2-tert-butylphenol (2.00 g, 13.3 mmol) in acetonitrile(30 ml) was dropwise added at −20° C. acetyl nitricate recovered bymixing together acetic anhydride (1.35 g, 13.3 mmol) and fuming nitricacid (13.3 mmol) at −0° C., with stirring for 5 minutes. The reactionsolution was diluted with water, and extracted with ethyl acetate. Theorganic layer was sequentially washed with water and saturated sodiumchloride solution and dried over anhydrous magnesium sulfate, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (60 g of silica gel; elutionsolvents:hexane:acetone=3:1), to recover 2-tert-butyl-6-nitrophenol (600mg at a yield of 23%) as a yellow crystal.

In the same manner as in Example 11 except for the use of2-tert-butyl-6-nitrophenol instead of3-hydroxy-6-methyl-2-nitropyridine, reaction progressed to recover theobjective compound as a colorless crystal.

Melting Point: 141-142° C. IR (KBr) cm⁻¹: 3247, 2961, 1654, 1505, 1117.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.57 (2H, m), 1.72 (2H, m),1.88 (2H, m), 2.36 (2H, m), 3.08 (2H, sept, J=6.8 Hz), 3.35 (2H, J=7.0Hz), 7.09 (2H, d, J=7.8 Hz), 7.18 (1H, dd, J=7.8, 1.4 Hz), 7.19 (1H, t,J=7.8 Hz), 7.23 (1H, t, J=7.8 Hz), 7.42 (1H, dd, J=7.8, 1.4 Hz), 8.71(1H, br s). EIMS m/z (relative intensity): 480 (M⁺, 100). ElementaryAnalysis: C₂₆H₄₀N₂O₂S Required: C, 72.46; H, 8.39; N, 5.83. Found: C,72.19; H, 8.35; N, 5.68.

Example 78 Production of6-(4,5,6-trimethoxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 1 except for the use of4,5,6-trimethoxy-2-mercaptobenzoxazole instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a pale yellow needle-like crystal.

Melting Point: 96-98° C. (dec.) IR (KBr) cm⁻¹: 3428, 3231, 2964, 1648,1485. 1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.9 Hz), 1.51-1.59 (2H, m),1.69-1.72 (2H, m), 1.81-1.89 (2H, m), 2.35 (2H, t, J=7.1 Hz), 3.08 (2H,sept, J=6.9 Hz), 3.30 (2H, t, J=7.1 Hz), 3.72 (3H, s), 3.82 (3H, s),4.18 (3H, S), 6.97 (1H, S), 7.09 (2H, d, J=7.8 Hz), 7.20 (1H, t, J=7.8Hz), 8.67 (1H, br s) EIMS m/z (relative intensity): 514 (M⁺, 100).Elementary Analysis: C₂₈H₃₈N₂O₅S Required: C, 65.34; H, 7.44; N, 5.44;S, 6.23. Found: C, 65.17; H, 7.45; N, 5.44; S, 6.26.

Example 79 Production of6-(7-ethoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

A solution of6-(7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(145 mg, 0.3 mmol) and 4-dimethylaminopyridine (3.7 mg, 0.03 mmol) inethanol (30 ml) was refluxed under heating for 24 hours. Afterconcentration, the reaction solution was diluted with water, andextracted with ethyl acetate. The organic layer was sequentially washedwith 0.05 N hydrochloric acid, water and saturated sodium chloridesolution and dried over anhydrous sodium sulfate, from which thesolvents were distilled off. The residue was purified by preparativethin layer chromatography (elution solvents:hexane:acetone=5:2), torecover the objective compound (95 mg at a yield of 64%) as a colorlessneedle-like crystal.

Melting Point: 114-116° C. IR (KBr) cm⁻¹: 3425, 3241, 2965, 1717, 1647.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.37 (3H, t, J=7.1 Hz),1.54-1.61 (2H, m), 1.69-1.76 (2H, m), 1.86-1.93 (2H, m), 2.36 (2H, t,J=7.2 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.2 Hz), 4.40 (2H,q, J=7.1 Hz), 7.09 (2H, d, J=7.8 Hz), 7.19 (1H, t, J=7.8 Hz), 7.42 (1H,t. J=7.8 Hz), 7.79 (1H, dd, J=7.8, 1.2 Hz), 7.83 (1H, dd, J=7.8, 1.2Hz), 8.70 (1H, br s). EIMS m/z (relative intensity): 496 (M⁺), 67 (100).Elementary Analysis: C₂₈H₃₆N₂O₄S Required: C, 67.71; H, 7.31; N, 5.64;S, 6.46. Found: C, 67.83; H, 7.33; N, 5.63; S, 6.52.

Example 80 Production of6-(7-methoxymethylcarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(141 mg, 0.3 mmol) in DMF (2 ml) were added triethylamine (36 mg, 0.36mmol) and chloromethyl methyl ether (27 mg, 0.33 mmol), and theresulting mixture was stirred at ambient temperature for 50 minutes. Thereaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over anhydrous sodiumsulfate, from which the solvents were distilled off. The residue waspurified by silica gel column chromatography (10 g of silica gel;elution solvents:hexane:acetone=5:2), to recover the objective compound(119 mg at a yield of 77%) as a colorless needle-like crystal.

Melting Point: 120-122° C. IR (KBr) cm⁻¹: 3433, 3241, 2963. 1729, 1649.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.54-1.61 (2H, m),1.64-1.76(2H, 1.86-1.93 (2H, m), 2.35-2.38 (2H, m), 3.08 (2H, sept, J=6.8 Hz),3.40 (2H, t, J=7.1 Hz), 3.52 (3H, s), 5.50 (2H, s), 7.09 (2H, d, J=7.8Hz), 7.19 (1H, t, J=7.8 Hz), 7.44 (1H, t, J=7.8 Hz), 7.83 (1H, dd,J=7.8, 1.2 Hz) 7.86 (1H, dd, J=7.8, 1.2 Hz), 8.70 (1H, br s) EIMS m/z(relative intensity): 512 (M⁺), 67 (100). Elementary Analysis:C₂₈H₃₆N₂O₂S Required: C, 65.60; H, 7.08; N, 5.46; S, 6.25. Found: C,65.69; H, 7.12; N, 5.42; S, 6.45.

Example 81 Production of6-(7-tert-butoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a suspension of6-(7-carboxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(141 mg, 0.3 mmol) in toluene (3 ml) was dropwise addedN,N-dimethylformamide-di-tert-butyl acetal (305 mg, 1.5 mmol) withstirring at 100° C. The reaction mixture in solution was left to standand cooled and was then diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over sodium sulfate, fromwhich the solvents were distilled off. The residue was crystallized fromhexane-ether-acetone, to recover the objective compound (130 mg at ayield of 83%) as a colorless needle-like crystal.

Melting Point: 137-140° C. IR (KBr) cm⁻¹: 3256, 2967, 1713, 1651, 1505.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.54-1.62 (2H, m), 1.60(9H, s), 1.68-1.76 (2H, m), 1.84-1.92 (2H, m), 2.36 (2H, t, J=6.6 Hz),3.08 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.0 Hz), 7.09 (2H, d, J=7.6Hz), 7.19 (1H, t, J=7.6 Hz), 7.39 (1H, t, J=7.8 Hz), 7.73 (1H, dd,J=7.8, 1.2 Hz), 7.79 (1H, dd, J=7.8, 1.2 Hz), 8.70 (1H, br s). EIMS m/z(relative intensity): 524 (M⁺), 468 (100). Elementary Analysis:C₃₀H₄₀N₂O₄S Required: C, 68.67; H, 7.68; N, 5.34; S, 6.11. Found: C,68.70; H, 7.54; N, 5.33; S, 6.23.

Example 82 Production of6-(7-tert-butoxycarbonylmethyloxybenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 59 except for the use of tert-butylglycolic acid instead of N,N-dimethyl ethanolamine, reaction progressedto recover the objective compound as a colorless needle-like crystal.

Melting Point: 77-79° C. IR (KBr) cm⁻¹: 3244, 2964, 1755, 1735, 1647.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.45 (9H, s), 1.52-1.62(2H, m), 1.64-1.74 (2H, m), 1.84-1.92 (2H, m), 2.36 (2H, t, J=6.8 Hz),3.08 (2H, sept, J=6.8 Hz), 3.40 (2H, t, J=7.0 Hz), 4.81 (2H, s), 7.09(2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.45 (1H, t, J=7.8 Hz), 7.84(1H, dd, J=7.8, 1.2 Hz), 7.87 (1H, dd, J=7.8, 1.2 Hz), 8.70 (1H, br s).EIMS m/z (relative intensity): 582 (M⁺), 525 (100). Elementary Analysis:C₃₂H₄₂N₂O₆S Required: C, 65.95; H, 7.26; N, 4.81; S, 5.50. Found: C,66.09; H, 7.29; N, 4.78; S, 5.53.

Example 83 Production of6-[7-(3-methyloxethan-3-ylmethyloxycarbonyl)benzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 59 except for the use of3-methyl-3-oxethane methanol instead of N,N-dimethyl ethanolamine,reaction progressed to recover the objective compound (340 mg at a yieldof 60%) as a colorless needle-like crystal.

Melting Point: 145-147° C. IR (KBr) cm⁻¹: 3425, 3254, 2965, 1722, 1647.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.40 (3H, s), 1.52-1.62(2H, m), 1.64-1.76 (2H, m), 1.84-1.92 (2H, m), 2.36 (2H, t, J=6.9 Hz),3.08 (2H, sept, J=6.8 Hz), 3.39 (2H, t, J=7.0 Hz), 4.32 (2H, d, J=5.9Hz), 4.47 (2H, s), 4.54 (2H, J=5.9 Hz), 7.09 (2H, d, J=7.6 Hz), 7.20(1H, t, J=7.6 Hz), 7.44 (1H, t, J=8.0 Hz), 7.83 (1H, dd, J=8.0, 1.2 Hz),7.85 (1H, dd, J=8.0, 1.2 Hz), 8.70 (1H, br s). EIMS m/z (relativeintensity): 552 (M⁺), 230 (100). Elementary Analysis: C₃₁H₄₀N₂O₅SRequired: C, 69.50; H, 7.34; N, 6.00; S, 6.87. Found: C, 69.47; H, 7.33;N, 6.08; S, 6.95.

Example 84 Production of6-[7-(4,4-dimethyloxazolin-2-yl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

6-(7-Methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(241 mg, 0.5 mmol) was added to 2-amino-2-methyl-1-propanol (3 ml), withstirring at 100° C. for 6 hours. The reaction solution was diluted withwater, and extracted with ethyl acetate. The organic layer wassequentially washed with diluted hydrochloric acid, water, an aqueoussodium hydrogen carbonate solution and saturated sodium chloridesolution and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (20 g of silica gel; elutionsolvents:hexane:acetone=5:2), to recover6-[7-[N-(1-hydroxy-2-methyl-2propyl)carbamoyl]benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide(140 mg at a yield of 52%) as a pale yellow needle-like crystal.

The amide (108 mg, 0.2 mmol) was added to phosphorus oxychloride (1 ml)under cooling in ice bath, and the resulting mixture was stirred at thetemperature for 10 minutes. The reaction mixture was poured into icebath water, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solutionand dried over anhydrous sodium sulfate, from which the solvents weredistilled off. The resulting residue was purified by preparative thinlayer chromatography (elution solvents; hexane:acetone=5:3), to recoverthe objective compound (67 mg at a yield of 64%) as a colorlessneedle-like crystal.

Melting Point: 127-129° C. IR (KBr) cm⁻¹: 3430, 3261, 2964, 1652, 1505.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.33 (6H, s), 1.52-1.62(2H, m), 1.66-1.76 (2H, m), 1.86-1.94 (2H, m), 2.36 (2H, t, J=6.8 Hz),3.08 (2H, sept, J=6.8 Hz), 3.37 (2H, t, J=7.2 Hz), 4.13 (2H, s), 7.09(2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.37 (1H, t, J=7.9 Hz), 7.71(1H, dd, J=7.9, 1.2 Hz), 7.72 (1H, dd, J=7.9, 1.2 Hz), 8.70 (1H, br s).EIMS m/z (relative intensity): 521 (M⁺), 262 (100). Elementary Analysis:C₃₀H₃₉N₃O₃S Required: C, 69.07; H, 7.53; N, 8.05; S, 6.15. Found: C,69.05; H, 7.56; N, 7.95; S, 6.24.

Example 85 Production of6-[7-([1,3]dioxolan-2-yl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

To a solution of6-(7-hydroxymethylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide(440 mg, 1.0 mmol) in methylene chloride (10 ml) were sequentially addedmolecular sieves 4A (powder, 2 g) and pyridinium dichromate (1.1 g, 2.9mmol), and the resulting mixture was stirred at ambient temperature for30 minutes. The reaction mixture was diluted with ether and filtered offthrough celite; and the filtrate was concentrated. The residue waspurified by silica gel column chromatography (20 g of silica gel;elution solvents; hexane:acetone=5:3), to recover6-(7-formylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (330mg at a yield of 75%) as a colorless needle-like crystal.

To a solution of the aldehyde (136 mg, 0.3 mmol) in toluene (5 ml) weresequentially added ethylene glycol (130 mg, 2.1 mmol), trimethylo-formate (133 mg, 0.9 mmol) and p-toluenesulfonic acid.monohydrate (10mg, 0.05 mmol), with stirring at 50° C. for 4 hours and additionally at100° C. for 4 hours. The resulting reaction solution was diluted withwater, and extracted with ethyl acetate. The organic layer was washedsequentially with an aqueous saturated sodium hydrogen carbonatesolution, water and saturated sodium chloride solution and dried overanhydrous sodium sulfate, from which the solvents were distilled off.The residue was purified by preparative thin layer chromatography(elution solvents:hexane:acetone=5:2), to recover a solid matter; then,the solid matter was crystallized from hexane-ether, to recover theobjective compound (76 mg at a yield of 51%) as a colorless needle-likecrystal.

Melting Point: 105-107° C. IR (KBr) cm⁻¹: 3432, 3221, 2963, 1643, 1537.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.61 (2H, m),1.67-1.76 (2H, m), 1.82-1.91 (2H, m), 2.36 (2H, t, J=6.9 Hz), 3.08 (2H,sept, J=6.8 Hz), 3.36 (2H, t, J=7.2 Hz), 3.98-4.13 (4H, m), 6.11 (1H,s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.30 (1H, t, J=7.6Hz), 7.34 (1H, dd, J=7.6, 1.6 Hz), 7.59 (1H, dd, J=7.6, 1.6 Hz), 8.70(1H, br s). EIMS m/z (relative intensity): 496 (M⁺,100). ElementaryAnalysis: C₂₈H₃₆N₂O₄S Required: C, 67.71; H, 7.31; N, 5.64; S, 6.46.Found: C, 67.88; H, 7.31; N, 5.62; S, 6.61.

Example 86 Production of6-[7-(4R,5R)-4,5-dimethyl[1,3]dioxolan-2-yl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 85 except for the use of(2R,3R)-2,3-butanediol instead of ethylene glycol, reaction progressedto recover the objective compound (101 mg at a yield of 64%) as acolorless needle-like crystal.

Melting Point: 115-117° C. IR (KBr) cm⁻¹: 3424, 3236, 2969, 1646, 1499.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.27-1.33 (6H, m),1.52-1.62 (2H, m), 1.66-1.76 (2H, m), 1.86-1.94 (2H, m), 2.36 (2H, t,J=6.2 Hz), 3.08 (2H, sept, J=6.8 Hz), 3.36 (2H, t, J=7.2 Hz), 3.79-3.87(2H, m), 6.21 (1H, s), 7.09 (2H, d, J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz),7.30 (1H, t, J=7.6 Hz), 7.35 (1H, dd, J=7.6, 1.4 Hz), 7.58 (1H, dd,J=7.6, 1.4 Hz), 8.70 (1H, br s). EIMS m/z (relative intensity): 524(M⁺), 452 (100). Elementary Analysis: C₃₀H₄₀N₂O₄S Required: C, 68.67; H,7.68; N, 5.34; S, 6.11. Found: C, 68.87; H, 7.68; N, 5.28; S, 6.24.

Example 87 Production of6-(7-acetylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

Potassium o-ethyl dithiocarbonate (241 mg, 1.5 mmol) was added to asolution of 3-amino-2-hydroxyacetophenone (113 mg, 0.75 mmol) in ethanol(10 ml), at reflux under heating for 16 hours, from which the solventwas distilled off. The residue was dissolved in water, followed byaddition of 2 N hydrochloric acid to adjust the resulting solution to pH3 to 4. The deposited crystal was filtered and recovered; then, thecrystal was washed with water and dried with heating under reducedpressure, to recover 7-acetyl-2-mercaptobenzoxazole (134 mg at a yieldof 92%) as a brown solid.

In the same manner as in Example 1 except for the use of the oxazoleherein recovered instead of 2-mercaptooxazolo[4,5-b]pyridine, reactionprogressed to recover the objective compound as a colorless needle-likecrystal.

Melting Point: 156-158° C. IR (KBr) cm⁻¹: 3437, 3218, 2958, 1682, 1651.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.62 (2H, m),1.66-1.76 (2H, m), 1.86-1.94 (2H, m), 2.37 (2H, t, J=6.9 Hz), 2.69 (3H,s), 3.08 (2H, sept, J=6.8 Hz), 3.40 (2H, t, J=7.0 Hz), 7.09 (2H, d,J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.42 (1H, t, J=7.8 Hz), 7.75 (1H, dd,J=7.8, 1.1 Hz), 7.82 (1H, dd, J=7.8, 1.1 Hz), 8.71 (1H, br s). EIMS m/z(relative intensity): 466 (M⁺), 177 (100). Elementary Analysis:C₂₇H₃₄N₂O₃S Required: C, 69.50; H, 7.34; N, 6.00; S, 6.87. Found: C,69.47; H, 7.33; N, 6.08; S, 6.95.

Example 88 Production of6-[7-(pyrazol-3-yl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

To a solution of6-(7-acetylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide (155mg, 0.33 mmol) in DMF (3 ml) was addedN,N-dimethylformamide-dimethylacetal (191 mg, 1.6 mmol), with stirringat 50° C. for 4 hours and additionally at 100° C. for 15 hours. Thereaction solution was diluted with water, and extracted with ethylacetate. The organic layer was sequentially washed with water andsaturated sodium chloride solution and dried over sodium sulfate, fromwhich the solvent was distilled off. The residue was purified bypreparative thin layer chromatography (elutionsolvents:hexane:acetone=5:3), to recover6-[7-(3-dimethylaminoacryloyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide(146 mg at a yield of 85%) as a pale yellow needle-like crystal.

To a solution of the enamine (104 mg, 0.2 mmol) in methanol (3 ml) wereadded acetic acid (60 mg, 1.0 mmol) and hydrazine.monohydrate (50 g, 1.0mmol), with stirring at ambient temperature for 2 hours. The reactionsolution was concentrated and then diluted with water, and extractedwith ethyl acetate. The organic layer was sequentially washed with waterand saturated sodium chloride solution and dried over sodium sulfate,from which the solvents were distilled off. The residue was purified bypreparative thin layer chromatography (elutionsolvents:hexane:acetone=1:1), to recover the objective compound (75 mgat a yield of 76%) as a colorless needle-like crystal.

Melting Point: 174-176° C. IR (KBr) cm⁻¹: 3236, 2964, 1647, 1530, 1493.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.62 (2H, m),1.66-1.76 (2H, m), 1.86-1.94 (2H, m), 2.37 (2H, t, J=6.9 Hz), 3.08 (2H,sept, J=6.8 Hz), 3.40 (2H, t, J=6.7 Hz), 6.81 (1H, m), 7.09 (2H, d,J=7.6 Hz), 7.19 (1H, t, J=7.6 Hz), 7.30 (1H, t, J=7.6 Hz), 7.34 (1H, m),7.52 (1H, m), 7.75-7.80 (2H, m), 8.70 (1H, br s), 12.79 (1H, br s). EIMSm/z (relative intensity): 490 (M⁺), 176 (100). Elementary Analysis:C₂₈H₃₆N₂O₄S Required: C, 68.54; H, 6.98; N, 11.42; S, 6.53. Found: C,68.65; H, 7.05; N, 11.30; S, 6.57.

Example 89 Production of6-[6,7-bis(methoxycarbonyl)benzoxazol-2-ylthio]-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 1 except for the use of 6,7-bis(methoxycarbonyl)-2-mercaptobenzoxazole instead of2-mercaptooxazolo[4,5-b]pyridine, reaction progressed to recover theobjective compound as a colorless needle-like crystal.

Melting Point: 159-161° C. IR (KBr) cm⁻¹: 3425, 3257, 1744, 1721, 1647.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.52-1.60 (2H, m),1.68-1.75 (2H, m), 1.85-1.92 (2H, m), 2.36 (2H, t, J=7.1 Hz), 3.08 (2H,sept, J=6.8 Hz), 3.40 (2H, t, J=7.1 Hz), 3.85 (3H, s), 3.91 (3H, s),7.09 (2H, d, J=7.6 Hz), 7.20 (1H, t, J=7.6 Hz), 7.77 (1H, d, J=8.3 Hz),7.81 (1H, d, J=8.3 Hz), 8.67 (1H, br s) EIMS m/z (relative intensity):540 (M⁺), 162 (100). Elementary Analysis: C₂₉H₃₆N₂O₆S Required: C,64.42; H, 6.71; N, 5.18. Found: C, 64.56; H, 6.69; N, 5.26.

Example 90 Production of6-(oxazolo[4,5-g]phthalid-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

To a solution of 2,3-bis(methoxycarbonyl)phenol (4.6 g, 20 mmol) inacetonitrile (100 ml) was dropwise added at 0° C. acetyl nitricate acidrecovered by mixing together acetic anhydride (6.0 g, 60 mmol) andfuming nitric acid (3.6 g, 60 mmol) at 0° C., with stirring for 40minutes. The reaction solution was diluted with water, and extractedwith ethyl acetate. The organic layer was sequentially washed with waterand saturated sodium chloride solution and dried over anhydrousmagnesium sulfate, from which the solvents were distilled off. Theresidue was purified by silica gel column chromatography (100 g ofsilica gel; elution solvents:hexane:acetone=5:2), to preferentiallyrecover 2,3-bis(methoxycarbonyl)-6-nitrophenol (1.34 g at a yield of32%) as a yellow crystal from ether.

To a solution of the diester (1.27 g, 5 mmol) in THF (4 ml) and t-BuOH(4 ml) in mixture was added an aqueous solution of lithium hydroxide(420 mg, 10 mmol) at 0° C., with stirring at ambient temperature for 24hours. The reaction solution was adjusted to acidity by using 2 Nhydrochloric acid, and extracted with ethyl acetate. The organic layerwas sequentially washed with water and saturated sodium chloridesolution and dried over anhydrous magnesium sulfate, from which thesolvents were distilled off, to recover3-hydroxy-2-methoxycarbonyl-4-nitrobenzoic acid (728 mg at a yield of60%) as a yellow crystal.

To a THF solution of the benzoic acid (650 mg, 2.7 mmol) was dropwiseadded borane (1.0 M THF solution, 8.1 ml, 8.1 mmol) at 0° C. under argonatmosphere, with stirring at ambient temperature for 24 hours. Thereaction solution was diluted with water and adjusted to acidity byusing 2 N hydrochloric acid, and extracted with ethyl acetate. Theorganic layer was sequentially washed with water and saturated sodiumchloride solution and dried over anhydrous magnesium sulfate, from whichthe solvents were distilled off. The residue was purified by silica gelcolumn chromatography (20 g of silica gel; elutionsolvents:chloroform:methanol=20:1), to recover6-nitro-7-hydroxyphthalide (290 mg at a yield of 61%) as a yellowcrystal.

To a solution of the nitrophthalide (290 mg, 1.5 mmol) in ethanol (20ml) was added a catalyst 10% palladium-carbon (300 mg), and theresulting mixture was stirred at ambient temperature under hydrogenatmosphere for 3 hours. The reaction solution was subjected tofiltration through celite. Potassium o-Ethyl dithiocarbonate (280 mg,1.7 mmol) was added to the resulting filtrate, with stirring underheating for 16 hours. After the solution was left to stand and cooled,the solvents were distilled off under reduced pressure. The residue wasdiluted with 2 N hydrochloric acid to adjust the resulting solution toacidity, and extracted with ethyl acetate. The organic layer wassequentially washed with water and saturated sodium chloride solution,and was then dried over anhydrous magnesium sulfate, from which thesolvents were distilled off. The residue was purified by silica gelcolumn chromatography (15 g of silica gel; elutionsolvents:chloroform:methanol=20:1). The resulting solid was crystallizedfrom acetone and hexane, to recover 2-mercaptooxazolo[4,5-g]phthalide(225 mg at a yield of 80%) as a colorless needle-like crystal.

In the same manner as in Example 1 except for the use of the phthalideherein recovered instead of 2-mercaptooxazolo[4,5-b]pyridine, reactionprogressed to recover the objective compound as a colorless needle-likecrystal.

Melting Point: 161-162° C. IR (KBr) cm⁻¹: 3243, 2959, 1768, 1647, 1263.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.56 (2H, m), 1.72 (2H, m),1.89 (2H, m), 2.47 (2H, m), 3.08 (2H, sept, J=7.0 Hz), 3.40 (2H, t,J=7.0 Hz), 5.57 (2H, s), 7.09 (2H, d, J=7.4 Hz), 7.18 (1H, t, J=7.4 Hz),7.78 (2H, m), 8.71 (1H, br, s). EIMS m/z (relative intensity): 480 (M⁺),162 (100). Elementary Analysis: C₂₇H₃₂N₂O₄S Required: C, 67.47; H, 6.71;N, 5.83; Found: C, 67.37; H, 6.75; N, 5.78;

Example 91 Production of6-[6-hydroxy-7-methoxycarbonylbenzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 77 except for the use of ethyl2,6-dihydroxybenzoate instead of 2-tert-butylphenol, reaction progressedto recover the objective compound as a colorless crystal.

Melting Point: 155-156° C. IR (KBr) cm⁻¹: 3228, 2966, 1677, 1645, 1513.1H-NMR (d₆-DMSO) δ: 1.11 (12H, d, J=6.8 Hz), 1.55 (2H, m), 1.71 (2H, m),1.86 (2H, m), 2.35 (2H, m), 3.08 (2H, sept, J=7.0 Hz), 3.32 (2H, t,J=7.0 Hz), 3.97 (3H, s), 6.92 (1H, d, J=8.7 Hz), 7.09 (2H, d, J=7.4 Hz),7.20 (1H, t, J=7.4 Hz), 7.67 (1H, d, J=8.7 Hz), 8.69 (1H, br, s). EIMSm/z (relative intensity): Elementary Analysis: C₂₇H₃₄N₂O₅S.1/2H₂ORequired: C, 63.88; H, 6.95; N, 5.52; Found: C, 63.93; H, 6.87; N, 5.37;

Example 92 Production of6-[6,7-dihydro-7,7-dimethyloxazolo[4,5-g]benzofuran]-2-ylthio-N-(2,6-diisopropylphenyl)hexanamide

In the same manner as in Example 77 except for the use of2,3-dihydro-2,2-dimethyl-7-benzofuranol instead of 2-tert-butylphenol,reaction progressed to recover the objective compound as a colorlesscrystal.

Melting Point: 136-137° C. IR (KBr) cm⁻¹: 3417, 3249, 2984, 1648, 1509.1H-NMR (d₆-DMSO) δ: 1.12 (12H, d, J=6.8 Hz), 1.49 (6H, s), 1.51-1.61(2H, m), 1.66-1.76 (2H, m), 1.80-1.88 (2H, m), 2.36 (2H, t, J=6.6 Hz),3.08 (2H, sept, J=6.8 Hz), 3.12 (2H, s), 3.33 (2H, t, J=7.1 Hz), 7.02(2H, d, J=7.8 Hz), 7.09 (2H, d, J=7.8 Hz), 7.09 (2H, d, J=7.6 Hz), 7.19(1H, t, J=7.6 Hz), 8.70 (1H, br s) EIMS m/z (relativeintensity):494(M⁺), 176(100) Elementary Analysis: C₂₉H₃₈N₂O₃S Required:C, 70.41; H, 7.74; N, 5.66; Found: C, 70.36; H, 7.64; N, 5.75;

Industrial Applicability

As has been described above, the novel anilide compound of the inventionis useful in the form of pharmaceutical composition, specifically asacyl coenzyme A cholesterol acyltransferase (ACAT) inhibitor.

What is claimed is:
 1. A compound represented by the following formulaIV, a salt thereof or a solvated product thereof:

X represents —NH—, oxygen atom or sulfur atom; Y represents —NR₄—,oxygen atom, sulfur atom, sulfoxide or sulfone; Z represents singlebond; R₁, R₂ and R₃ may be the same or different and represent hydrogenatom, a lower alkyl group, a lower alkoxyl group, halogen atom, hydroxylgroup, phosphate group, sulfonamide group, or amino group which may ormay not have a substituent; otherwise, any combination of two of R₁, R₂and R₃ represents an alkylene dioxy group; R₄ represents hydrogen atom,a lower alkyl group, an aryl group or a silylated lower alkyl groupwhich may or may not have a substituent; and R₉, R₁₀, R₉′, R₁₀′,R₉″R₁₀″, R₉′″, and R₁₀′″, may be the same or different and representhydrogen atom, a lower alkyl group which may or may not have asubstituent, a lower alkoxyl group which may or may not have asubstituent, halogen atom, hydroxyl group, carboxyl group, analkoxycarbonyl group which may or may not have a substituent, analkylcarbonyloxy group which may or may not have a substituent, analkylcarbonyl group which may or may not have a substituent, carbamoylgroup which may or may not have a substituent, a hydroxyalkyl group,phosphate group, sulfonamide group, amino group which may or may nothave a substituent, an aminoalkyl group which may or may not have asubstituent, or a heterocyclic residue; otherwise, any combination oftwo thereof represents an alkylene dioxy group; and n represents aninteger of 2 to 15; with the proviso that when X is sulfur atom then


2. A pharmaceutical composition comprising a compound, a salt thereof ora solvated compound thereof according to claim 1, and a pharmaceuticallyacceptable carrier.
 3. A pharmaceutical composition according to claim2, which is an ACAT inhibitor, an intra-cellular cholesterol transferinhibitory agent, a blood cholesterol-reducing agent or a macrophagefoaming-suppressing agent.
 4. A pharmaceutical composition according toclaim 2, which is prophylactic and therapeutic agent of hyperlipidemia,arteriosclerosis, cerebrovascular diseases, ischemic cardiac diseases,ischemic intestinal diseases or aortic aneurysm.
 5. A method fortherapeutically treating diseases with the etiology of abnormal levelsof ACAT, intra-cellular cholesterol transfer, blood cholesterol ormacrophage foaming, comprising administering a therapeutically effectivedose of a compound according to Formula (I), a salt thereof or asolvated compound thereof:

 represents a divalent residue of pyridine which may or may not have asubstituent; and Ar represents an aryl group which may or may not have asubstituent; X represents —NH—, oxygen atom or sulfur atom; Y represents—NR₄—, oxygen atom, sulfur atom, sulfoxide or sulfone; Z representssingle bond; R₄ represents hydrogen atom, a lower alkyl group, an arylgroup or a silylated lower alkyl group which may or may not have asubstituent; and n represents an integer of 1 to
 15. 6. A method fortherapeutically treating hyperlipidemia, arteriosclerosis, ischemiccardiac diseases, ischemic intestinal diseases or aortic aneurysm,comprising administering a therapeutically effective dose of a compoundaccording to Formula (I), a salt thereof or a solvated compound thereof;

 represents a divalent residue of pyridine which may or may not have asubstituent; Ar represents an aryl group which may or may not have asubstituent; x represents —NH—, oxygen atom or sulfur atom; Y represents—NR₄, oxygen atom, sulfur atom, sulfoxide or sulfone; Z represent singlebond; R₄ represents hydrogen atom, a lower alkyl group, an aryl group ora silylated lower alkyl group which ay or may not have a substituent;and n represents an integer of 1 to
 15. 7. A method of claim 5 whereinthe compound of Formula (I), salt thereof or solvated compound thereofis administered to a patient suffering from a disease having etiology ofabnormal levels of ACAT intra-cellular cholesterol transfer, bloodcholesterol or macrophage foaming.
 8. A method of claim 5 wherein thecompound of Formula (I), salt thereof or solvated compound thereof isadministered to a patient suffering from a disease having etiology ofabnormal levels of ACAT.
 9. A method of claim 5 wherein the compound ofFormula (I), salt thereof or solvated compound thereof is administeredto a patient suffering from a disease associated with abnormal levels ofintra-cellular cholesterol transfer.
 10. A method of claim 5 wherein thecompound of Formula (I), salt thereof or solvated compound thereof isadministered to a patient suffering from a disease associated withabnormal levels of blood cholesterol or macrophage foaming.
 11. A methodof claim 5 wherein the compound of Formula (I), salt thereof or solvatedcompound thereof is administered to a patient suffering from a diseaseassociate with abnormal levels of macrophage foaming.
 12. A method ofclaim 6 wherein the compound of Formula (I), salt thereof or solvatedcompound thereof is administered to a patient suffering fromhyperlipidemia, arteriosclerosis, an ischemic cardiac disease, anischemic intestinal disease or aortic aneurysm.
 13. A method of claim 6wherein the compound of Formula (I), salt thereof or solvated compoundthereof is administered to a patient suffering from hyperlipidemia. 14.A method of claim 6 wherein the compound of Formula (I), salt thereof orsolvated compound thereof is administered to a patient suffering fromarteriosclerosis.
 15. A method of claim wherein the compound of Formula(I), salt thereof or solvated compound thereof is administered to apatient suffering from an ischemic cardiac disease.
 16. A method ofclaim 6 wherein the compound of Formula (I), salt thereof or solvatedcompound thereof is administered to a patient suffering from an ischemicintestinal disease.
 17. A method of claim 6 wherein the compound ofFormula (I), salt thereof or solvated compound thereof is administeredto a patient suffering from aortic aneurysm.